2-Quinoxalinol Salen Compounds and Uses Thereof

ABSTRACT

Disclosed are 2-quinoxalinol salen compounds and in particular 2-quinoxalinol salen Schiff-base ligands. The disclosed 2-quinoxalinol salen compounds may be utilized as ligands for forming complexes with cations, and further, the formed complexes may be utilized as catalysts for oxidation reactions. The disclosed 2-quinoxalinol salen compounds also may be conjugated to solid supports and utilized in methods for selective solid-phase extraction or detection of cations.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. provisional application No. 61/125,489, filed on Apr. 25,2008; U.S. provisional application No. 61/190,239, filed on Aug. 27,2008; and U.S. provisional application No. 61/196,305, filed on Oct. 16,2008; the contents of which are incorporated herein by reference intheir entireties.

BACKGROUND

The present subject matter relates to 2-quinoxalinol salen compounds andin particular 2-quinoxalinol salen Schiff-base compounds. In particular,the disclosed 2-quinoxalinol salen compounds may be utilized as ligandsfor forming complexes with cations.

Salen ligands have been of interest to a wide variety of chemists. Inparticular, these have been investigated in a variety of applicationsbecause of their ease of preparation and ability to form stablecomplexes. For example, copper (I) salen complexes have beeninvestigated as antitumor agents and protein kinase inhibitors. Salenligands and their complexes also have been applied as catalysts in avariety of processes including as catalytic scavengers of hydrogenperoxide and cytoprotective agents, in the catalytic oxidation ofsecondary amines, in enantioselective catalysts for asymmetricepoxidation of unfunctionalized olefins or as catalysts for ring-openingmetathesis. As catalysts, these complexes have proven quite useful, inparticular after incorporation into solid supports and for chiral orstereoselective reaction catalysis. Therefore, new salen ligands aredesirable.

Salen ligands are the product of a salicylic aldehyde compound and anethylene diamine compound, hence the name “salen” is derived. Therefore,under suitable reaction conditions new ethylene diamine compounds may beutilized to create new salen ligands. 2-quinoxalinol is an ethylenediamine compound that previously has not been utilized for forming salenligands. Derivatives of 2-quinoxalinols are key intermediates asbioactive agents in agriculture, have been used in dyes, and have beenkey pharmaceutical or medicinal intermediates. Synthetic methods for theparallel synthesis of 2-quinoxalinols have been previously reported.These factors have served to peak interest in utilizing 2-quinoxalinolsfor the preparation of a new series of 2-quinoxalinol salen frameworkligands based on a Schiff base synthesis. The development of preparativemethods using solution-phase parallel synthesis is not only feasible,but also desirable in the development of a new series of metalcomplexing agents that could be screened for bioactivity, or used in thedevelopment of new catalysts or metal selective sensors or sensingmaterials, through the incorporation of a unique coordination site and aquinoxaline that should have high UV and fluorescent activity. Takingadvantage of a solution-phase combinatorial approach allows for thepreparation of a series of ligands with a variety of substitutionpatterns. Here, it also is demonstrated that 2-quinoxalinols exhibitregioselectivity in Schiff base synthesis of salen ligands, whichpermits formation of asymmetrically substituted 2-quinoxalinol salenligands.

SUMMARY

Disclosed are 2-quinoxalinol salen compounds and in particular2-quinoxalinol salen Schiff-base ligands. The disclosed 2-quinoxalinolsalen compounds may be utilized as ligands for forming complexes withcations. The formed complexes may be utilized as catalysts for oxidationreactions. Further, the disclosed 2-quinoxalinol salen compounds may beconjugated to solid supports and utilized in methods for selectivesolid-phase extraction or detection of cations.

In some embodiments, the disclosed compounds have a formula:

where R₁ is an amino acid side chain moiety and R₂ and R₃ are hydrogen,hydroxyl, C₁₋₆ alkyl which may be straight chain or branched (e.g.,3-tert-butyl or 3,5-Di-tert butyl), C₁₋₆ alkoxy which may be straightchain or branched, ether, or amine. The substituents R₂ and R₃ may bethe same or different. In some embodiments, at least one of R₂ and R₃ is3-OH or at least one of R₂ and R₃ is 5-OH. Salt forms of the disclosedcompounds also are contemplated, for example salts of the dioxoanion arecontemplated:

where M²⁺ is a divalent metal cation. Typically, the disclosed compoundsare fluorescent.

The substituent R₁ is an amino acid side chain moiety, which may be aside chain moiety of a naturally occurring amino acid or a non-naturallyoccurring amino acid. In some embodiments, R₁ is selected from:

In other embodiments, R₁ may be selected from:

Preferably, R₁ is a side chain that increases the UV-Visible extinctioncoefficient of the compounds or that increases fluorescence of thecompounds.

The disclosed compounds may form complexes with metal cations. In someembodiments, the disclosed compounds are complexed to a divalent cation,which may include, but is not limited to Cu²⁺, Mn²⁺, Co²⁺, Ni²⁺, UO₂ ²⁺,Fe²⁺, Pd²⁺, Ag²⁺, and Sn²⁺, or mixtures thereof. In some embodiments,the complexes may be formed by first forming the salen compound andsubsequently reacting the compound with a divalent cation.Alternatively, the compound may be formed in a reaction mixture thatcomprises the divalent cation.

The disclosed compounds and complexes may be conjugated to a solidsupport. Suitable solid supports may include functionalized resins,which may include, but are not limited to functionalized polystyereneand polyethylene resins. Suitable functionalized polystyrene resinsinclude, but are not limited to, aminomethyl polystyrene resin,2-chlorotrityl chloride resin, DHP HM resin, HMPA-AM resin, Knorr resin,Knorr-2-chlorotrityl resin, MBHA resin, Merrifield resin, oxime resin,PAM resin, Rink amide-AM resin, Rink amide-MBHA resin, Sieber resin,Wang resin, Weinreb AM resin, Boc-Ser-Merrifield resin, andBoc-Gly-Merrifield resin. Optionally, the disclosed compounds may beconjugated to the solid support via a linker compound such as anacylating linker compound. Suitable acylating linker compounds mayinclude, but are not limited to, anhydride compounds such as acidanhydrides.

The disclosed compounds and complexes typically are fluorescent. In someembodiments, the disclosed compounds and complexes may be conjugated toadditional fluorophores. The additional fluorophores optionally may befunctionalized prior to conjugation with the disclosed compounds andcomplexes.

Also disclosed are methods for making the disclosed compounds. In someembodiments, the methods include reacting a reaction mixture comprisinga 2-quinoxalinol compound, analog, or derivative having a formula:

where R₁ is an amino acid side chain moiety; and a salicylic aldehyde,compound, analog, or derivative having a formula:

where R₂ is hydrogen, hydroxyl, C₁₋₆ alkyl which may be straight chainor branched (e.g., 3-tert-butyl or 3,5-Di-tert butyl), C₁₋₆ alkoxy whichmay be straight chain or branched, ether, or amine, thereby obtainingthe salen compound. The 2-quinoxalinol compound, analog, or derivativeand salicylic aldehyde compound, analog, or derivative may be present inthe reaction mixture at a suitable ratio. For example, in someembodiments the reaction mixture comprises about equal molar amounts ofthe 2-quinoxalinol compound, analog, or derivative and the salicylicaldehyde compound, analog, or derivative. In other embodiments, thereaction mixture comprises an excess amount of the salicylic aldehydecompound, analog, or derivative as compared to the 2-quinoxalinolcompound, analog, or derivative.

In some embodiments, the methods may include obtaining or isolating anintermediate compound having a formula:

and reacting the intermediate in a reaction mixture with a salicylicaldehyde analog or derivative having a formula:

where R₂ and R₃ are hydrogen, hydroxyl, C₁₋₆ alkyl which may be straightchain or branched (e.g., 3-tert-butyl or 3,5-Di-tert butyl), C₁₋₆ alkoxywhich may be straight chain or branched, ether, or amine, therebyobtaining the salen compound. The substituents R₂ and R₃ may be the sameor different in order to obtain a symmetrically substituted orasymmetrically substituted salen compound, respectively. Optionally, thereaction mixtures include an alcohol (e.g., MeOH) and reacting includesheating the reaction mixture.

Also disclosed are methods for utilizing the disclosed compounds. Insome embodiments, the compounds may be utilized for removing a cationfrom a solution. Suitable cations for the removal methods may includediavalent cations such as Cu²⁺, Mn²⁺, Co²⁺, Ni²⁺, UO₂ ²⁺, Fe²⁺, Pd²⁺,Ag²⁺, and Sn²⁺, and mixtures thereof. Optionally, the compounds may beconjugated to a solid support prior to their use in the removal methods.

Also disclosed are methods for detecting a cation in a solution, whichmethods may include detecting divalent cations. The method may include:(a) contacting the solution with a salen compound, which optionally maybe conjugated to a solid support or a fluorophore, where if the solutioncomprises the cation, the compound forms a complex with the cation; and(b) detecting the complex in the solution. The complex may be detectedby methods which may include, but are not limited to, detecting a changein an absorption maximum for the solution, detecting a change influorescence of the compound (or detecting a change in fluorescence ofan optionally conjugated fluorophore), or detecting a change inelectrochemical properties of the solution.

In other embodiments, the methods for detecting a cation in a solutionmay include: (a) contacting the solution with complex comprising acomplexed cation as disclosed herein, which complex optionally may beconjugated to a solid support or a fluorophore, where if the solutioncomprises the cation, the solution cation displaces the complexed cationfrom the compound and forms a new complex with the compound; and (b)detecting the new complex or detecting the displaced cation. In themethods, the new complex and displaced cation may be detected by stepswhich may include, but are not limited to, detecting a change in anabsorption maximum for the solution, detecting a change in fluorescenceof the compound (or detecting a change in fluorescence of an optionallyconjugated fluorophore), or detecting a change in electrochemicalproperties of the solution.

In some embodiments, the formed complexes may be utilized as catalystsin chemical reactions. For example, the formed complexes may be utilizedin oxidation reactions, which may include but are not limited to,oxidation reactions of methylenes (e.g., aryl, allyl, vinyl, or anyother α,β-unsaturated methylene), asymmetric epoxidation reactions,ring-opening reactions of epoxides, and oxidation reactions of amines.In some embodiments, methods for oxidizing compounds include reacting amethylene compound, an oxidizing agent, and a 2-quinoxalinol salencomplex.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. illustrates the yield (%) for different salen compounds usingvarious ratios of 2-quinoxalinol compounds and salicylic aldehydecompounds.

FIG. 2. provides ¹H-NMR results from Example 2 of intermediate (1a) and2-quinoxalinol imines (3ae). For intermediate (1a), ¹H-NMR of hydrogenof two amino groups is shown. For 2-quinoxalinol imine (3ae), only thehydrogen on the carbon of imine group is shown.

FIG. 3. is a bar graph of Cu²⁺ extraction indicating the different molarratios of PLG1(2) resin to Cu²⁺ extracted quantified using atomicabsorption.

FIG. 4. is a bar graph of Cu²⁺ extraction with PLG1(2) resin withrespect to agitation time quantified using atomic absorption.

FIG. 5. is a bar graph of Cu²⁺ recovery with PLG1(2) resin versus timequantified using atomic absorption.

FIG. 6. illustrates the structures of salen, salph, and salqu coppercomplex catalysts (1-7)

FIG. 7. illustrates the yield for oxidation of diphenylmethane intobenzophenone in acetonitrile for several oxidants. Yields are based onpurification by flash column chromatography.

FIG. 8. illustrates the yield for oxidation of diphenylmethane intobenzophenone in acetonitrile for various ratios of catalyst. Yields arebased on purification by flash column chromatography.

FIG. 9. illustrates the yield for oxidation of diphenylmethane intobenzophenone in acetonitrile versus time. Yields are based onpurification by flash column chromatography.

FIG. 10. illustrates the yield for oxidation of diphenylmethane intobenzophenone in acetonitrile for various ratios of oxidant. Yields arebased on purification by flash column chromatography.

FIG. 11. illustrates reaction yields using copper salts or ligandsupported metal catalysts (salen, salph, and salqu ligands). Yields arebased on separation by flash column chromatography.

DETAILED DESCRIPTION

The disclosed subject matter is further described below.

Unless otherwise specified or indicated by context, the terms “a”, “an”,and “the” mean “one or more.”

As used herein, “about”, “approximately,” “substantially,” and“significantly” will be understood by persons of ordinary skill in theart and will vary to some extent on the context in which they are used.If there are uses of the term which are not clear to persons of ordinaryskill in the art given the context in which it is used, “about” and“approximately” will mean plus or minus ≦10% of the particular term and“substantially” and “significantly” will mean plus or minus >10% of theparticular term.

As used herein, the terms “include” and “including” have the samemeaning as the terms “comprise” and “comprising.”

Disclosed herein are salen compounds. As used herein, a “salen” refersto a compound formed from a salicylic aldehyde compound (which mayinclude salicylic aldehyde analogs or derivative) and an ethylenediamine compound (which may include ethylene diamine analogs orderivatives). As disclosed herein, salicylic aldehyde analogs orderivatives may include compounds having a formula:

where R₂ is hydrogen, hydroxyl, C₁₋₆ alkyl which may be straight chainor branched (e.g., 3-tert-butyl or 3,5-Di-tert butyl), C₁₋₆ alkoxy whichmay be straight chain or branched, ether, or amine. As disclosed herein,an ethylene diamine analog or derivative may include 2-quinoxalinol oran analog or derivative thereof such as a compound having a formula:

where R₁ is an amino acid side chain side chain moiety. Analogs of2-quinoxalinol and methods for making and using such analogs are knownin the art. (See, e.g., Zhang et al., J. Comb. Chem. 2004, 6, 431-436;and Wu et al., Molec. Diversity, 8: 165-174, 2004; the contents of whichare incorporated herein by reference in their entireties including theirdisclosure related to analogs of analogs of 2-quinoxalinol and methodsfor making and using such analogs). Salen compounds and the use thereof(e.g., as ligands) also are known in the art. (See, e.g., U.S. Pat. Nos.7,122,537; 6,982,243; 6,903,043; 6,884,750; 6,828,293; 6,794,526;6,723,879; 6,720,434; 6,713,435; 6,689,733; and 6,589,948; and U.S.Published Application Nos. 2009-0030172; 2007-0123503; 2005-0085401;2004-0059107; 2004-0054201; 2003-0216250; 2003-0139627; 2003-0120091;2003-0100763; and 2003-0032821; the contents of which are incorporatedby reference in their entireties including their disclosure related tosalen compounds and their use as ligands for metal cations).

Salt forms of the disclosed salen compounds also are contemplated. Forexample, salt forms may include deprotonated forms of the salencompounds having a formula:

(i.e., the dioxoanion form), which optionally is bound ionically to acation, M²⁺, which optionally is a divalent metal cation. Salt forms maybe prepared by methods that include lithiation in order to form alithium salt of the disclosed salen compound, for example, a compoundhaving a formula:

The lithium salt of the disclosed salen compound further may be reactedwith a metal chloride salt MCl₂ to form a metal salt of the salencompound having a formula:

In some embodiments, M²⁺ is a lanthanide metal such as gadolinium. Thesemetal salts of the disclosed salen compounds may be utilized ascatalysts in reactions that require C—H activation or in polymerizationreactions.

Typically, the disclosed salen compounds are fluorescent. For example,when stimulating by light having a wavelength of 365 nm, 385 nm, 405 nm,415 nm, or 546 nm, the compounds emit light having a wavelength within arange of 300-900 nm. In particular, two emission bands may be observedat 395 nm and 480 nm.

The disclosed salen compounds may be prepared from 2-quinoxalinolcompounds, analogs, or derivatives reacted with salicylic aldehydecompounds, analogs, or derivatives. The 2-quinoxalinol compound,analogs, or derivatives may be prepared from natural or non-naturallyamino acids. (See, e.g., Zhang et al., J. Comb. Chem. 2004, 6, 431-436;and Wu et al., Molec. Diversity, 8: 165-174, 2004; the contents of whichare incorporated herein by reference in their entireties including theirdisclosure related to analogs or derivative of 2-quinoxalinol andmethods for making and using such analogs.) Accordingly, the disclosedsalen compounds may include a substituent R₁ which is a side chainmoiety of an amino acid. As disclosed herein, an “amino acid” refers toany naturally occurring or non-naturally occurring amino acid. Naturallyoccurring amino acids include the twenty (20) common amino acids (i.e.,glycine, alanine, leucine, isoleucine, valine, phenylalanine, serine,threonine, cysteine, methionine, tyrosine, asparagine, glutamine,aspartic acid, glutamic acid, tryptophan, histidine, lysine, arginine,and proline), and pyrrolysine and selenocysteine. In some embodiments,the disclosed salen compounds may include a substituent R₁ selectedfrom:

Preferably, R₁ is a side chain moiety that increases the UV-Visibleextinction coefficient of the salen compounds or that increasesfluorescence of the salen compounds. For example, R₁ may be an aromaticamino acid side chain moiety. Suitable, aromatic amino acid side chainmoieties may comprise at least one 5- or 6-membered carbocyclic orheterocyclic ring, where the heterocyclic ring may be substituted withheteroatoms that include, but are not limited to, N, O, and S. In someembodiments, R₁ is a side chain moiety of a non-naturally occurringamino acid that increases the UV-Visible extinction coefficient of thesalen compounds or that increases fluorescence of the salen compounds.For example, in some embodiments, R₁ may comprise naphthalene,anthracene, quinoline, quinoxaline, acridine, pyrimidine, pyridine,quinazoline, pyridazine, imidazole, indazole, indole, acenaphthylene,fluorine, phenanthrene, chrysene, pyrene, quinine, or anthraquinone.

Non-naturally occurring amino acids may be prepared by derivatizing anaturally occurring amino acid. In some embodiments, a non-naturallyoccurring amino acid may be derivatizing by conjugating to the sidechain moiety of a naturally occurring amino acid a compound selectedfrom naphthalene, anthracene, quinoline, quinoxaline, acridine,pyrimidine, pyridine, quinazoline, pyridazine, imidazole, indazole,indole, acenaphthylene, fluorine, phenanthrene, chrysene, pyrene,quinine, or anthraquinone. The non-naturally occurring amino acidthereby obtained may be utilized in the methods disclosed herein forsynthesizing 2-quinoxalinol analogs. (See, e.g., Zhang et al., J. Comb.Chem. 2004, 6, 431-436; and Wu et al., Molec. Diversity, 8: 165-174,2004; the contents of which are incorporated herein by reference intheir entireties including their disclosure related to analogs orderivative of 2-quinoxalinol and methods for making and using suchanalogs). For example, the non-naturally occurring amino acid therebyobtained having a formula:

where R₁ is defined as above and R₄ is hydrogen or C₁₋₆ alkyl which maybe straight chain or branched (e.g., Me or Et) may be reacted with1,5-difluoro-2,4-dinitrobenzene having a formula:

to obtain a compound having a formula:

This compound further may be reacted with ammonia to obtain a compoundhaving a formula:

This compound further may be reduced and cyclized to obtain a2-quinoxalinol compound, analog, or derivative having a formula:

The 2-quinoxalinol compound, analog, or derivative thereby obtained maybe utilized to prepare the presently disclosed salen compounds.Non-naturally occurring amino acids for use in preparing the disclosed2-quinoxalinol compounds, analogs, and derivatives are known in the artand are described, e.g., in U.S. Pat. Nos. 7,468,458 and 7,385,038; andin U.S. Published Application Nos. 2009-0093405, 2009-0036525,2006-0246509, 2006-0234339, 2004-0265952, 2004-0259256, and2003-0235852, the contents of which are incorporated by reference hereinin their entireties including their disclosure related to non-naturallyoccurring amino acids. Amino acids that are suitable for preparing thedisclosed 2-quinoxalinol compounds, analogs, or derivatives may includenatural or synthetic L-amino acids and D-amino acids. Derivatives ofnaturally occurring amino acids for preparing 2-quinoxalinol compounds,analogs, or derivatives also are available commercially. (See, e.g.,Sigma-Aldricht Catalog, the content of which is incorporated byreference in its entirety including disclosure related to amino acidderivatives).

Derivatives of alanine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to(R)-(+)-α-Allylalanine, (S)-(−)-α-Allylalanine, D-2-Aminobutyric acid,L-2-Aminobutyric acid, 2-Aminoisobutyric acid,(S)-(+)-2-Amino-4-phenylbutyric acid, Boc-Abu-OH, Boc-D-Abu-OH,Boc-Aib-OH, Boc-β-(9-anthryl)-Ala-OH, Boc-β-(3-benzothienyl)-Ala-OH,Boc-β-(3-benzothienyl)-D-Ala-OH, Boc-Cha-OH, Boc-D-Cha-OH, Boc-Cha-OMe,Boc-β-(2-furyl)-Ala-OH, Boc-β-(2-furyl)-D-Ala-OH, Boc-β-iodo-Ala-OBzl,Boc-β-iodo-D-Ala-OBzl, Boc-3-iodo-D-Ala-OMe, Boc-β-iodo-Ala-OMe,Boc-β-Nal-OH, Boc-D-1-Nal-OH, Boc-2-Nal-OH, Boc-D-2-4a1-OH,(R)-Boc-3-(2-naphthyl)-β-Ala-OH, (S)-Boc-3-(2-naphthyl)-β-Ala OH,Boc-β-phenyl-Phe-OH, Boc-3-(1-pyrazolyl)-Ala-OH,Boc-3-(2-pyridyl)-Ala-OH, Boc-3-(3-pyridyl)-Ala-OH,(S)-Boc-3-(3-pyridyl)-β-Ala-OH, Boc-3-(3-pyridyl)-D-Ala-OH,Boc-3-(4-pyridyl)-Ala-OH, Boc-3-(4-pyridyl)-D-Ala-OH,Boc-β-2-quinolyl)-Ala-OH, Boc-3-(2-quinolyl)-DL-Ala-OH,Boc-3-(3-quinolyl)-DL-Ala-OH, Boc-3-(4-quinolyl)-DL-Ala-OH,Boc-3-(2-quinoxalyl)-DL-Ala-OH, Boc-β-styryl-Ala-OH,Boc-β-styryl-D-Ala-OH, Boc-β-(4-thiazolyl)-Ala-OH,Boc-β-(2-thienyl)-Ala-OH, Boc-β-(2-thienyl)-D-Ala-OH,Boc-β-(3-thienyl)-Ala-OH, Boc-β-(3-thienyl)-D-Ala-OH,Boc-3-(1,2,4-triazol-1-yl)-Ala-OH,3-(5-Carboxy-2H-benzotriazol-2-yl)-L-alanine, 3-Cyclohexyl-D-alanine,3-Cyclopentyl-DL-alanine,(−)-3-(3,4-Dihydroxyphenyl)-2-methyl-L-alanine, 3,3-Diphenyl-D-alanine,3,3-Diphenyl-L-alanine,N—[(S)-(+)-1-(Ethoxycarbonyl)-3-phenylpropyl]-L-alanine,N-[1-(S)-(+)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl, Fmoc-Abu-OH,Fmoc-3-(9-anthryl)-Ala-OH, Fmoc-β-(3-benzothienyl)-Ala-OH,Fmoc-β-(3-benzothienyl)-D-Ala-OH, Fmoc-Cha-OH, Fmoc-D-Cha-OH,Fmoc-3-cyclopentyl-DL-Ala-OH, Fmoc-β-(2-furyl)-Ala-OH,Fmoc-β-(2-furyl)-D-Ala-OH, Fmoc-α-Me-Ala-OH, Fmoc-1-Nal-OH,Fmoc-D-1-Nal-OH, Fmoc-2-Nal-OH, Fmoc-D-2-Nal-OH, Fmoc-β-phenyl-Phe-OH,Fmoc-3-(1-pyrazolyl)-Ala-OH, Fmoc-β-(2-pyridyl)-Ala-OH,Fmoc-β-(2-pyridyl)-D-Ala-OH, Fmoc-β-(3-pyridyl)-Ala-OH,Fmoc-β-(3-pyridyl)-D-Ala-OH, Fmoc-β-(4-pyridyl)-Ala-OH,Fmoc-β-(4-pyridyl)-D-Ala-OH, Fmoc-3-(2-quinolyl)-DL-Ala-OH,Fmoc-β-styryl-Ala-OH, Fmoc-β-styryl-D-Ala-OH,Fmoc-β-(4-thiazolyl)-Ala-OH, Fmoc-β-(2-thienyl)-Ala-OH,Fmoc-β-(3-thienyl)-Ala-OH, Fmoc-β-(3-thienyl)-D-Ala-OH,Fmoc-3-(1,2,4-triazol-1-yl)-Ala-OH, N-(3-lndolylacetyl)-L-alanine,3-(2-Naphthyl)-D-alanine, 3-(2-Oxo-1,2-dihydro-4-quinolinyl)alanine,3-(1-Pyrazolyl)-L-alanine, 3-(2-Pyridyl)-D-alanine,3-(2-Pyridyl)-L-alanine, 3-(3-Pyridyl)-D-alanine,3-(3-Pyridyl)-L-alanine, 3-(4-Pyridyl)-D-alanine,3-(4-Pyridyl)-L-alanine, 3-(2-Quinolyl)-DL-alanine,3-(4-Quinolyl)-DL-alanine, 3-(2-Tetrazolyl)-L-alanine,3-(2-Thienyl)-L-alanine, 3-(2-Thienyl)-DL-alanine, L-Thyroxine,3-(1,2,4-Triazol-1-yl)-L-alanine, 3,3,3-Trifluoro-DL-alanine, and3-Ureidopropionic acid. The 2-quinoxalinol compounds, analogs, orderivatives thereby obtained may be utilized to prepare the presentlydisclosed salen compounds.

Derivatives of arginine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,L-2-Amino-3-guanidinopropionic acid hydrochloride, 4-Guanidinobutyricacid, and NωNitro-L-arginine benzyl ester p-toluenesulfonate salt. The2-quinoxalinol compounds, analogs, or derivatives thereby obtained maybe utilized to prepare the presently disclosed salen compounds.

Derivatives of asparagine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,Boc-Asn(Xan)-OH. The 2-quinoxalinol compounds, analogs, or derivativesthereby obtained may be utilized to prepare the presently disclosedsalen compounds.

Derivatives of aspartic acid for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,N-Z-L-aspartic acid. The 2-quinoxalinol compounds, analogs, orderivatives thereby obtained may be utilized to prepare the presentlydisclosed salen compounds.

Derivatives of cysteine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,L-Cystathionine, L-Cysteic acid, L-Cysteinesulfinic acid,Se-Methyl-seleno-L-cysteine, Seleno-L-cystine,S-(2-Thiazolyl)-L-cysteine, S-(2-Thienyl)-L-cysteine, andS-(4-Tolyl)-L-cysteine. The 2-quinoxalinol compounds, analogs, orderivatives thereby obtained may be utilized to prepare the presentlydisclosed salen compounds.

Derivatives of glutamic acid for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,D-2-Aminoadipic acid, γ-Carboxy-DL-glutamic acid, and4-Fluoro-DL-glutamic acid. The 2-quinoxalinol compounds, analogs, orderivatives thereby obtained may be utilized to prepare the presentlydisclosed salen compounds.

Derivatives of glutamine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,Boc-Cit-OH, Boc-D-Cit-OH, D-Citrulline, Fmoc-Cit-OH, andThio-L-citrulline. The 2-quinoxalinol compounds, analogs, or derivativesthereby obtained may be utilized to prepare the presently disclosedsalen compounds.

Derivatives of histidine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,N-Boc-3-(3-methyl-4-nitrobenzyl)-L-histidine methyl ester. The2-quinoxalinol compounds, analogs, or derivatives thereby obtained maybe utilized to prepare the presently disclosed salen compounds.

Derivatives of isoleucine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,Boc-allo-Ile-OH, D-allo-Isoleucine, and DL-allo-Isoleucine. The2-quinoxalinol compounds, analogs, or derivatives thereby obtained maybe utilized to prepare the presently disclosed salen compounds.

Derivatives of leucine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,N-[(2S,3R)-3-Amino-2-hydroxy-4-phenylbutyryl]-L-leucine,Boc-4,5-dehydro-Leu-OH (dicyclohexylammonium) salt, Boc-Ile-OSu,N-(3,5-Dinitrobenzoyl)-DL-leucine, Fmoc-tBu-Gly-OH,N-(3-Indolylacetyl)-L-isoleucine, D-tert-Leucine, L-tert-Leucine,DL-tert-Leucine, L-tert-Leucine methyl ester, and5,5,5-Trifluoro-DL-leucine. The 2-quinoxalinol compounds, analogs, orderivatives thereby obtained may be utilized to prepare the presentlydisclosed salen compounds.

Derivatives of lysine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,DL-5-Hydroxylysine, and (5R)-5-Hydroxy-L-lysine. The 2-quinoxalinolcompounds, analogs, or derivatives thereby obtained may be utilized toprepare the presently disclosed salen compounds.

Derivatives of phenylalanine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,4-Amino-L-phenylalanine, Boc-Bpa-OH, Boc-D-Bpa-OH,Boc-4-tert-butyl-Phe-OH, Boc-4-tert-butyl-D-Phe-OH,Boc-4-(Fmoc-amino)-L-phenylalanine, (S)-Boc-4-methoxy-β-Phe-OH,Boc-pentafluoro-D-phenylalanine, Boc-Pentafluoro-L-phenylalanine,Boc-Phe(4-Br)—OH, Boc-D-Phe(4-Br)—OH, Boc-Phe(2-CF3)-OH,Boc-D-Phe(2-CF3)-OH, Boc-Phe(3-CF3)-OH, Boc-D-Phe(3-CF3)-OH,Boc-Phe(4-CF3)-OH, Boc-D-Phe(4-CF3)-OH, Boc-Phe(2-Cl)—OH,Boc-D-Phe(2-Cl)—OH, Boc-Phe(2,4-Cl2)-OH, Boc-D-Phe(2,4-Cl2)-OH,Boc-D-Phe(3-Cl)—OH, Boc-Phe(3,4-Cl2)-OH, Boc-D-Phe(3,4-Cl2)-OH,Boc-Phe(4-Cl)—OH, Boc-D-Phe(4-Cl)—OH, Boc-Phe(2-CN)—OH,Boc-D-Phe(2-CN)—OH, Boc-Phe(3-CN)—OH, Boc-D-Phe(3-CN)—OH,Boc-Phe(4-CN)—OH, Boc-D-Phe(4-CN)—OH, Boc-Phe(2-Me)—OH,Boc-D-Phe(2-Me)—OH, Boc-Phe(3-Me)—OH, Boc-D-Phe(3-Me)—OH,Boc-Phe(4-Me)—OH, Boc-D-Phe(4-Me)—OH, Boc-Phe(4-NH2)-OH,Boc-Phe(4-NO2)-OH, Boc-D-Phe(4-NO2)-OH, Boc-Phe(2-F)—OH,Boc-D-Phe(2-F)—OH, Boc-Phe(3-F)—OH, Boc-D-Phe(3-F)—OH,Boc-Phe(3,4-F2)-OH, Boc-D-Phe(3,4-F2)-OH, Boc-Phe(3,5-F2)-OH,Boc-Phe(4-F)—OH, Boc-D-Phe(4-F)—OH, Boc-Phe(4-I)—OH, Boc-D-Phe(4-I)—OH,4-Borono-D-phenylalanine, 4-Borono-L-phenylalanine,4-Borono-DL-phenylalanine, 4-Borono-DL-phenylalanine,p-Bromo-DL-phenylalanine, 4-Bromo-L-phenylalanine,N-(tert-Butoxycarbonyl)-β-phenyl-D-phenylalanine,4-Chloro-L-phenylalanine, DL-3,5-Difluorophenylalanine,3,4-Dihydroxy-L-phenylalanine, 3,4-Dihydroxy-L-phenylalanine,3,4-Dihydroxy-DL-phenylalanine, 3-(3,4-Dimethoxyphenyl)-L-alanine,o-Fluoro-D-phenylalanine, o-Fluoro-L-phenylalanine,o-Fluoro-DL-phenylalanine, m-Fluoro-L-phenylalanine,m-Fluoro-DL-phenylalanine, m-Fluoro-DL-phenylalanine,p-Fluoro-D-phenylalanine, p-Fluoro-D-phenylalanine,p-Fluoro-L-phenylalanine, p-Fluoro-L-phenylalanine,p-Fluoro-DL-phenylalanine, p-Fluoro-DL-phenylalanine,D-4-Fluorophenylalanine, L-4-Fluorophenylalanine, Fmoc-Bpa-OH,Fmoc-D-Bpa-OH, Fmoc-pentafluoro-L-phenylalanine,Fmoc-Phe(4-Boc2-guanidino)-OH, Fmoc-Phe(4-Br)—OH, Fmoc-Phe(2-CF3)-OH,Fmoc-D-Phe(2-CF3)-OH, Fmoc-Phe(3-CF3)-OH, Fmoc-D-Phe(3-CF3)-OH,Fmoc-Phe(4-CF3)-OH, Fmoc-D-Phe(4-CF3)-OH, Fmoc-Phe(2-Cl)—OH,Fmoc-D-Phe(2-Cl)—OH, Fmoc-Phe(2,4-Cl2)-OH, Fmoc-D-Phe(2,4-Cl2)-OH,Fmoc-Phe(3,4-Cl2)-OH, Fmoc-D-Phe(3,4-Cl2)-OH, Fmoc-Phe(4-Cl)—OH,Fmoc-D-Phe(4-Cl)—OH, Fmoc-Phe(2-CN)—OH, Fmoc-D-Phe(2-CN)—OH,Fmoc-Phe(3-CN)—OH, Fmoc-D-Phe(3-CN)—OH, Fmoc-Phe(4-CN)—OH,Fmoc-Phe(2-Me)—OH, Fmoc-D-Phe(2-Me)—OH, Fmoc-Phe(3-Me)—OH,Fmoc-D-Phe(3-Me)—OH, Fmoc-Phe(4-Me)—OH, Fmoc-D-Phe(4-Me)—OH,Fmoc-Phe(4-NO2)-OH, Fmoc-Phe(2-F)—OH, Fmoc-D-Phe(2-F)—OH,Fmoc-Phe(3-F)—OH, Fmoc-D-Phe(3-F)—OH, Fmoc-Phe(3,4-F2)-OH,Fmoc-D-Phe(3,4-F2)-OH, Fmoc-Phe(3,5-F2)-OH, Fmoc-Phe(4-F)—OH,Fmoc-D-Phe(4-F)—OH, Fmoc-Phe(4-I)—OH, Fmoc-D-Phe(4-I)—OH,Fmoc-4-(phosphonomethyl)-Phe-OH, 6-Hydroxy-DL-DOPA,4-(Hydroxymethyl)-D-phenylalanine, N-(3-Indolylacetyl)-L-phenylalanine,p-Iodo-D-phenylalanine, 4-Iodo-L-phenylalanine,α-Methyl-D-phenylalanine, α-Methyl-L-phenylalanine,α-Methyl-DL-phenylalanine, β-Methyl-DL-phenylalanine,α-Methyl-DL-phenylalanine, 4-Nitro-D-phenylalanine,4-Nitro-DL-phenylalanine, 4-Nitro-L-phenylalanine,4-Nitro-L-phenylalanine, (S)-(+)-4-Nitrophenylalanine methyl ester,2-(Trifluoromethyl)-D-phenylalanine,2-(Trifluoromethyl)-L-phenylalanine,3-(Trifluoromethyl)-D-phenylalanine,3-(Trifluoromethyl)-L-phenylalanine,4-(Trifluoromethyl)-D-phenylalanine,4-(Trifluoromethyl)-L-phenylalanine, and 3,3′,5-Triiodo-L-thyronine. The2-quinoxalinol compounds, analogs, or derivatives thereby obtained maybe utilized to prepare the presently disclosed salen compounds.

Derivatives of serine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,N-Benzoyl-(2R,3S)-3-phenylisoserine, L-Isoserine, DL-Isoserine,DL-Isoserine, and DL-3-Phenylserine. The 2-quinoxalinol compounds,analogs, or derivatives thereby obtained may be utilized to prepare thepresently disclosed salen compounds.

Derivatives of threonine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,D-allo-Threonine, and L-allo-Threonine. The 2-quinoxalinol compounds,analogs, or derivatives thereby obtained may be utilized to prepare thepresently disclosed salen compounds.

Derivatives of tryptophan for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,5-Fluoro-L-tryptophan, 5-Fluoro-DL-tryptophan, 5-Hydroxy-L-tryptophan,5-Methoxy-DL-tryptophan, 5-Methyl-DL-tryptophan, 5-Methyl-DL-tryptophan,and 6-Methyl-DL-tryptophan. The 2-quinoxalinol compounds, analogs, orderivatives thereby obtained may be utilized to prepare the presentlydisclosed salen compounds.

Derivatives of tyrosine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,3-Amino-L-tyrosine, Boc-Tyr(3, 5-12)—OSu, 3-Chloro-L-tyrosine,3,5-Diiodo-L-tyrosine, Fmoc-Tyr(3-NO2)-OH, Fmoc-Tyr(3, 5-12)—OH,α-Methyl-DL-tyrosine, α-Methyl-DL-tyrosine methyl ester,3-Nitro-L-tyrosine, 3-Nitro-L-tyrosine ethyl ester, DL-o-Tyrosine, andDL-m-Tyrosine. The 2-quinoxalinol compounds, analogs, or derivativesthereby obtained may be utilized to prepare the presently disclosedsalen compounds.

Derivatives of valine for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,3-Fluoro-DL-valine, (R)-(+)-α-Methylvaline, and (S)-(−)-α-Methylvaline.The 2-quinoxalinol compounds, analogs, or derivatives thereby obtainedmay be utilized to prepare the presently disclosed salen compounds.

Other suitable amino acids for preparing the disclosed 2-quinoxalinolcompounds, analogs, or derivatives may include, but are not limited to,2,4-Diaminobutyric Acid, 2,3-Diaminopropionic Acid, Norleucine,Norvaline, Ornithine, and Pyroglutamine, or analogs or derivativesthereof. The 2-quinoxalinol compounds, analogs, or derivatives therebyobtained may be utilized to prepare the presently disclosed salencompounds.

The disclosed salen compounds may function as ligands for cations suchas divalent metal cations. Divalent metal cations may include, but arenot limited to Cu²⁺, Mn²⁺, Co²⁺, Ni²⁺, UO₂ ²⁺, Fe²⁺, Pd²⁺, Ag²⁺, andSn²⁺, and mixtures thereof. In some embodiments, the complexes may beformed by first forming the salen compound and subsequently reacting thesalen compound with a divalent cation (i.e., in a two-step synthesismethod). Alternatively, the complex may be formed in a reaction mixturethat comprises the components for forming the salen compounds and thedivalent cation (i.e., in a one-step synthesis method). (See Example 4below.)

The disclosed salen compounds and complexes may be conjugated to a solidsupport. Suitable solid supports may include resins, which may beincorporated into filter cartridges or utilized in batch methods. Insome embodiments, suitable resins may include polystyrene resins orpolyethylene resins. The resins typically are functionalized (e.g., withone or more of an aminomethyl group, a 2-chlorotrityl group, an oximegroup, an amide group, or the like). Suitable functionalized polystyreneresins may include, but are not limited to, aminomethyl polystyreneresin, 2-chrlotrityl chloride resin, DHP HM resin, HMPA-AM resin, Knorrresin, Knorr-2-chlorotrityl resin, MBHA resin, Merrifield resin, oximeresin, PAM resin, Rink amide-AM resin, Rink amide-MBHA resin, Sieberresin, Wang resin, Weinreb AM resin, Boc-Ser-Merrifield resin, andBoc-Gly-Merrifield resin.

The disclosed salen compounds and complexes typically are fluorescent.However, the disclosed salen compounds and complexes may be conjugatedto additional fluorophores as known in the art. Suitable additionalfluorophores may include, but are not limited to, 1,5 IAEDANS; 1,8-ANS;4-Methylumbelliferone; 5-carboxy-2,7-dichlorofluorescein;5-Carboxyfluorescein (5-FAM); 5-Carboxytetramethylrhodamine (5-TAMRA);5-FAM (5-Carboxyfluorescein); 5-HAT (Hydroxy Tryptamine); 5-HydroxyTryptamine (HAT); 5-ROX (carboxy-X-rhodamine); 5-TAMIA(5-Carboxytetranethylrhodamine); 6-Carboxyrhodamine 6G; 6-CR 6G; 6-JOE;7-Amino-4-methylcoumarin; 7-Aminoactinomycin D (7-AAD);7-Hydroxy-4-methylcoumarin; 9-Amino-6-chloro-2-methoxyacridine; ABQ;Acid Fuchsin; ACMA (9-Amino-6-chloro-2-methoxyacridine); AcridineOrange; Acridine Red; Acridine Yellow; Acriflavin; Acriflavin FeulgenSITSA; Alexa Fluor 350™; Alexa Fluor 430™; Alexa Fluor 488™; Alexa Fluor532™; Alexa Fluor 546™; Alexa Fluor 568™; Alexa Fluor 594™; Alexa Fluor633™; Alexa Fluor 647™; Alexa Fluor 660™; Alexa Fluor 680™; AlizarinComplexon; Alizarin Red; Allophycocyanin (APC); AMC; AMCA-S; AMCA(Aminomethylcoumarin); AMCA-X; Aminoactinomycin D; Aminocoumarin;Aminomethylcoumarin (AMCA); Anilin Blue; Anthrocyl stearate; APC(Allophycocyanin); APC-Cy7; APTS; Astrazon Brilliant Red 4G; AstrazonOrange R; Astrazon Red 6B; Astrazon Yellow 7 GLL; Atabrine; ATTO-TAGTMCBQCA; ATTO-TAG™ FQ; Auramine; Aurophosphine G; Aurophosphine; BAO 9(Bisaminophenyloxadiazole); Berberine Sulphate; Beta Lactamase; BFP blueshifted GFP (Y66H); Blue Fluorescent Protein; BFP/GFP FRET; Bimane;Bisbenzamide; Bisbenzimide (Hoechst); Blancophor FFG; Blancophor SV;BOBOTM-1; BOBOTM-3; Bodipy 492/515; Bodipy 493/503; Bodipy 500/510;Bodipy 505/515; Bodipy 530/550; Bodipy 542/563; Bodipy 558/568; Bodipy564/570; Bodipy 576/589; Bodipy 581/591; Bodipy 630/650-X; Bodipy650/665-X; Bodipy 665/676; Bodipy FL; Bodipy FL ATP; Bodipy F1-Ceramide;Bodipy R6G SE; Bodipy TMR; Bodipy TMR-X conjugate; Bodipy TMR-X, SE;Bodipy TR; Bodipy TR ATP; Bodipy TR-X SE; BO-PRO™-1; BO-PRO™-3;Brilliant Sulphoflavin FF; Calcein; Calcein Blue; Calcium Crimson™;Calcium Green; Calcium Orange; Calcofluor White; Carboxy-X-rhodamine(5-ROX); Cascade Blue™; Cascade Yellow; Catecholamine; CCF2(GeneBlazer); CFDA; CFP-Cyan Fluorescent Protein; CFP/YFP FRET;Chlorophyll; Chromomycin A; CL-NERF (Ratio Dye, pH); CMFDA;Coelenterazine f; Coelenterazine fcp; Coelenterazine h; Coelenterazinehcp; Coelenterazine ip; Coelenterazine n; Coelenterazine O; CoumarinPhalloidin; C-phycocyanine; CPM Methylcoumarin; CTC; CTC Formazan; Cy2™;Cy3.1 8; Cy3.5™; Cy3™; Cy5.1 8; Cy5.5™; Cy5™; Cy7™; Cyan GFP; cyclic AMPFluorosensor (FiCRhR); Dabcyl; Dansyl; Dansyl Amine; Dansyl Cadaverine;Dansyl Chloride; Dansyl DHPE; Dansyl fluoride; DAPI; Dapoxyl; Dapoxyl 2;Dapoxyl 3; DCFDA; DCFH (Dichlorodihydrofluorescein Diacetate); DDAO; DHR(Dihydrorhodamine 123); Di-4-ANEPPS; Di-8-ANEPPS (non-ratio); DiA(4-Di-16-ASP); Dichlorodihydrofluorescein Diacetate (DCFH);DiD-Lipophilic Tracer; DiD (DiIC18(5)); DIDS; Dihydrorhodamine 123(DHR); DiI (DiIC18(3)); Dinitrophenol; DiO (DiOC18(3)); DiR; DiR(DiIC18(7)); DNP; Dopamine; DsRed; DTAF; DY-630-NHS; DY-635-NHS; EBFP;ECFP; EGFP; ELF 97; Eosin; Erythrosin; Erythrosin ITC; Ethidium Bromide;Ethidium homodimer-1 (EthD-1); Euchrysin; EukoLight; Europium (III)chloride; EYFP; Fast Blue; FDA; Feulgen (Pararosaniline); FITC; FlazoOrange; Fluo-3; Fluo-4; Fluorescein (FITC); Fluorescein Diacetate;Fluoro-Emerald; Fluoro-Gold (Hydroxystilbamidine); Fluor-Ruby; Fluor X;FM 1-43™; FM 4-46; Fura Red™; Fura Red™/Fluo-3; Fura-2; Fura-2/BCECF;Genacryl Brilliant Red B; Genacryl Brilliant Yellow 1OGF; Genacryl Pink3G; Genacryl Yellow 5GF; GeneBlazer (CCF2); GFP(S65T); GFP red shifted(rsGFP); GFP wild type, non-UV excitation (wtGFP); GFP wild type, WVexcitation (wtGFP); GFPuv; Gloxalic Acid; Granular Blue;Haematoporphyrin; Hoechst 33258; Hoechst 33342; Hoechst 34580; HPTS;Hydroxycoumarin; Hydroxystilbamidine (FluoroGold); Hydroxytryptamine;Indo-1; Indodicarbocyanine (DiD); Indotricarbocyanine (DiR); IntrawhiteCf; JC-1; JO-JO-1; JO-PRO-1; Laurodan; LDS 751 (DNA); LDS 751 (RNA);Leucophor PAF; Leucophor SF; Leucophor WS; Lissamine Rhodamine;Lissamine Rhodamine B; Calcein/Ethidium homodimer; LOLO-1; LO-PRO-1;Lucifer Yellow; Lyso Tracker Blue; Lyso Tracker Blue-White; Lyso TrackerGreen; Lyso Tracker Red; Lyso Tracker Yellow; LysoSensor Blue;LysoSensor Green; LysoSensor Yellow/Blue; Mag Green; Magdala Red(Phloxin B); Mag-Fura Red; Mag-Fura-2; Mag-Fura-5; Mag-Indo-1; MagnesiumGreen; Magnesium Orange; Malachite Green; Marina Blue; Maxilon BrilliantFlavin 10 GFF; Maxilon Brilliant Flavin 8 GFF; Merocyanin;Methoxycoumarin; Mitotracker Green FM; Mitotracker Orange; MitotrackerRed; Mitramycin; Monobromobimane; Monobromobimane (mBBr-GSH);Monochlorobimane; MPS (Methyl Green Pyronine Stilbene); NBD; NBD Amine;Nile Red; Nitrobenzoxadidole; Noradrenaline; Nuclear Fast Red; NuclearYellow; Nylosan Brilliant lavin E8G; Oregon Green; Oregon Green 488-X;Oregon Green™; Oregon Green™ 488; Oregon Green™ 500; Oregon Green™ 514;Pacific Blue; Pararosaniline (Feulgen); PBFI; PE-Cy5; PE-Cy7; PerCP;PerCP-Cy5.5; PE-TexasRed [Red 613]; Phloxin B (Magdala Red); PhorwiteAR; Phorwite BKL; Phorwite Rev; Phorwite RPA; Phosphine 3R;Phycoerythrin B [PE]; Phycoerythrin R [PE]; PKH26 (Sigma); PKH67; PMIA;Pontochrome Blue Black; POPO-1; POPO-3; PO—PRO-1; PO—PRO-3; Primuline;Procion Yellow; Propidium lodid (PI); PYMPO; Pyrene; Pyronine; PyronineB; Pyrozal Brilliant Flavin 7GF; QSY 7; Quinacrine Mustard; Red 613[PE-TexasRed]; Resorufin; RH 414; Rhod-2; Rhodamine; Rhodamine 110;Rhodamine 123; Rhodamine 5 GLD; Rhodamine 6G; Rhodamine B; Rhodamine B200; Rhodamine B extra; Rhodamine BB; Rhodamine BG; Rhodamine Green;Rhodamine Phallicidine; Rhodamine Phalloidine; Rhodamine Red; RhodamineWT; Rose Bengal; R-phycocyanine; R-phycoerythrin (PE); RsGFP; S65A;S65C; S65L; S65T; Sapphire GFP; SBFI; Serotonin; Sevron Brilliant Red2B; Sevron Brilliant Red 4G; Sevron Brilliant Red B; Sevron Orange;Sevron Yellow L; sgBFP™; sgBFP™ (super glow BFP); sgGFP™; sgGFP™ (superglow GFP); SITS; SITS (Primuline); SITS (Stilbene IsothiosulphonicAcid); SNAFL calcein; SNAFL-1; SNAFL-2; SNARF calcein; SNARFI; SodiumGreen; SpectrumAqua; SpectrumGreen; SpectrumOrange; Spectrum Red; SPQ(6-methoxy-N-(3-sulfopropyl)quinolinium); Stilbene; Sulphorhodamine Bcan C; Sulphorhodamine G Extra; SYTO 11; SYTO 12; SYTO 13; SYTO 14; SYTO15; SYTO 16; SYTO 17; SYTO 18; SYTO 20; SYTO 21; SYTO 22; SYTO 23; SYTO24; SYTO 25; SYTO 40; SYTO 41; SYTO 42; SYTO 43; SYTO 44; SYTO 45; SYTO59; SYTO 60; SYTO 61; SYTO 62; SYTO 63; SYTO 64; SYTO 80; SYTO 81; SYTO82; SYTO 83; SYTO 84; SYTO 85; SYTOX Blue; SYTOX Green; SYTOX Orange;Tetracycline; Tetramethylrhodamine (TRITC); Texas Red™; Texas Red-X™conjugate; Thiadicarbocyanine (DiSC3); Thiazine Red R; Thiazole Orange;Thioflavin 5; Thioflavin S; Thioflavin TCN; Thiolyte; Thiozole Orange;Tinopol CBS (Calcofluor White); TMR; TO-PRO-1; TO-PRO-3; TO-PRO-5;TOTO-1; TOTO-3; TriColor (PE-Cy5); TRITCTetramethylRodaminelsoThioCyanate; True Blue; TruRed; Ultralite; UranineB; Uvitex SFC; wt GFP; WW 781; X-Rhodamine; XRITC; Xylene Orange; Y66F;Y66H; Y66W; Yellow GFP; YFP; YO-PRO-1; YO-PRO-3; YOYO-1; and YOYO-3. Asused herein, a “fluorophore” may include a salt of the fluorophore or afunctionalized form of the fluorophore (e.g., where the fluorophore mayinclude one or more of an amino group, a 2-chlorotrityl group, an oximegroup, an amide group, or the like).

The disclosed salen compounds may be conjugated directly to the solidsupports or fluorophores disclosed herein (which optionally may befunctionalized) or may be conjugated via a linker compound. Suitablelinker compounds may include acylating compounds such as anhydridecompounds, and in particular acid anhydrides (e.g., glutaric anhydride).

The disclosed salen compounds may be prepared by reacting a reactionmixture comprising a 2-quinoxalinol compound, analog, or derivativehaving a formula:

where R₁ is an amino acid side chain moiety; and a salicylic aldehydeanalog or derivative having a formula:

where R₂ is hydrogen, hydroxyl, C₁₋₆ alkyl which may be straight chainor branched (e.g., 3-tert-butyl or 3,5-Di-tert butyl), C₁₋₆ alkoxy whichmay be straight chain or branched, ether, or amine, thereby obtainingthe salen compound. For example, in some embodiments the reactionmixture comprises about equal molar amounts of 2-quinoxalinol compound,analog, or derivative and salicylic aldehyde compound, analog, orderivative. In other embodiments, the reaction mixture comprises anexcess amount of salicylic aldehyde compound, analog, or derivative(e.g., at least 2.5×, 5×, 7.5×, or 10× as much salicylic aldehydecompound, analog, or derivative as compared to 2-quinoxalinol compound,analog, or derivative.)

The reaction mixture further comprises a solvent. Suitable solvents mayinclude alcohols (e.g, MeOH). The reaction mixture further may includean additional solvent such as dimethylformamide (DMF). The method mayinclude applying heat to the reaction mixture (e.g., heating to at leastabout 60° C., 70° C. or 80° C., for at least about 6, 8, 10, or 12hours).

The methods may include obtaining or isolating an intermediate compoundhaving a formula:

and reacting the intermediate in a reaction mixture with a salicylicaldehyde analog or derivative having a formula:

where R₂ and R₃ are hydrogen, hydroxyl, C₁₋₆ alkyl which may be straightchain or branched (e.g, 3-tert-butyl or 3,5-Di-tert butyl), C₁₋₆ alkoxywhich may be straight chain or branched, ether, or amine. Thesubstituents R₂ and R₃ may be the same or different, thereby obtaining asymmetrically or asymmetrically substituted salen compound,respectively. The reaction mixture further comprises a solvent. Suitablesolvents may include alcohols (e.g., MeOH). The reaction mixture furthermay include an additional solvent such as dimethylformamide (DMF). Themethod may include applying heat to the reaction mixture (e.g., heatingto at least about 60° C., 70° C. or 80° C., for at least about 6, 8, 10,or 12 hours).

Also disclosed are methods for detecting a cation in a solution, whichmay include detecting divalent metal cations such as UO₂ ²⁺. The methodmay include (a) contacting the solution with a salen compound, whichoptionally may be conjugated to a solid support or a fluorophore, whereif the solution comprises the cation, the compound forms a complex withthe cation; and (b) detecting the complex in the solution.

In other embodiments, the methods for detecting a cation in a solutionmay include: (a) contacting the solution with complex comprising acomplexed cation as disclosed herein, which complex optionally may beconjugated to a solid support or a fluorophore, where if the solutioncomprises the cation, the solution cation displaces the complexed cationfrom the compound and forms a new complex with the compound; and (b)detecting the new complex or detecting the displaced cation.

Detection methods for the complex (or new complex) or the displacedcation may include detecting a change in an absorption maximum for thesolution via UV-Vis spectra analysis (e.g., where the uncomplexedcompound exhibits a first absorption maximum and the complexed compoundexhibits a second different absorption maximum). Detection methods forthe complex (or new complex) or the displaced cation also may includedetecting a change in fluorescence from the compound, complex, oroptionally conjugated fluorophore (e.g., detecting a change inwavelength of absorbed or emitted light from the compound, complex, oroptionally conjugated fluorophore when the complex is formed). Detectionmethods for the complex (or new complex) or the displaced cation alsomay include detecting a change in electrochemical properties of thesolution (e.g., detecting a change in voltage of the solution if acomplex is formed or if a complexed cation is displaced by a cation insolution).

In some embodiments, the formed complexes may be utilized as catalystsin chemical reactions. For example, the formed complexes may be utilizedin oxidation reactions, which may include but are not limited to,oxidation reactions of methylenes (e.g., aryl, allyl, vinyl, or anyother α,β-unsaturated methylene), asymmetric epoxidation reactions,ring-opening reactions of epoxides, oxidation reactions of amines,hydrolytic kinetic resolution (HKR), Hetero Diels-Alder reactions,Pictet-Spengler reactions, and hydrocyanation reactions. In someembodiments, methods for oxidizing compounds include reacting amethylene compound, an oxidizing agent, and a 2-quinoxalinol salencomplex. As used herein, an “oxidizing agent” is any compound ormaterial which is capable of removing an electron from a compound beingoxidized. Suitable oxidizing agents include, but are not limited to,hydrogen peroxide, alkyl peroxides, peroxy acids, oxygen, and ozone.Optionally, the methylene compound to be oxidized may be may besubstituted with one or more heteroatoms (e.g., N or O), or with one ormore substituents (e.g., carbonyl, amino, formyl, ester, and nitro).Suitable methylene compounds may include, but are not limited to arylmethylene compounds.

EXAMPLES

The following EXAMPLES are illustrative and are not intended to limitthe scope of the claimed subject matter.

Example 1

Reference is made to Wu et al., “An Efficient Method for Solution-PhaseParallel Synthesis of 2-Quinoxalinol Salen Schiff-base Ligands,” J.Comb. Chem., 2007, 9 (4), pp. 601-608, the content of which isincorporated herein by reference in its entirety.

Abstract and Introduction

A solution-phase parallel method for the synthesis of 2-quinoxalinolsalen ligands was designed and optimized. The synthesis began withcommercially available 1,5-difluoro-2,4-dinitrobenzene (DFDNB) andemployed a sequence of five reaction steps. Laboratory techniques withlow sensitivity to water or air for solution-phase parallel reactionswere coupled with workup and purification procedures to give high-purityand yield a small ligand library of 20 compounds. The final step, aSchiff-base condensation of an aldehyde with the diaminoquinoxalineresults in a new category of ligands for use in metal coordination orfor use as potential bioagents, based on the skeleton2,2′-(1E,1′E)-(quinoxaline-6,7-diylbis(azan-1-yl-1-ylidene))bis(methan-1-yl-1-ylidene)diphenol.The approach described here is adaptable for parallel synthesis of alarger size library. A solution-phase parallel method of synthesizing a2-quinoxalinonl salen ligands and a preparative library for a series ofthese ligands was demonstrated.

Results and Discussion

Synthesis began with the preparation of a 2-quinoxalinol precursor.(See, e.g., Zhang et al., J Comb. Chem. 2004, 6, 431-436; and Wu et al.,Molec. Diversity, 8: 165-174, 2004. Based on this previous work, themethod for synthesizing diamino-2-quinoxalinols was further optimized.Here, scavenger resins as used in the previous investigations werereplaced by the use of 2 equivalents of DIPEA (diisopropylethylamine) toremove the produced HF and HCl on the amino acid methyl group in thefirst step (Scheme 1).

Ammonium hydroxide in water (3 equiv.) was employed in the substitutionof the second fluorine (Step 2, Scheme 1). In this way, the intermediate(3) does not require additional purification after substitution of thetwo fluorine atoms, because the remaining unreacted ammonium hydroxideand water can be removed using high vacuum. This serves both to simplifythe process of parallel solution methods and reduce the costs ofmaterials. After reduction by wet Pd on carbon, the targetintermediates, diamino-2-quinoxalinols (4), were recrystallized from 95%ethanol. The purity and yield of each aim intermediate were very high(Table 1).

TABLE 1 Synthesis results of diamino-2-quinoxalinols. No. Compound R₁Purity (%)^(‡) R_(t) (min) Yield (%)* mp (° C.) 1 4a

99 3.46 97 261.4~263.5 2 4b

99 3.53 90 234.5~244.5 3 4c

99 3.18 99 249.5~250.3 4 4d

99 3.47 68 >300 ^(‡)Identified by HPLC; R_(t) is retention time. *Onestep yield of Pd-C reduction.

Four different kinds of methyl amino acids were selected as the buildingblocks, including phenylalanine with an aromatic group, methioninecontaining a hetero atom (sulfur), and valine and leucine with alkylgroups at R₁. The yield of intermediate 4d (made from the methioninestarting material) was lower than others. The aldehydes chosen includedhydrophilic salicylaldehydes (di-hydroxide, 5a and 5b) and hydrophobicsalicylaldehyde (mono- and di-tert-butyl, 5c and 5d) to build thelibrary. The selected salicylic aldehydes provided a variety ofcompounds of varying solubility and coordination properties for thesalen product in metal coordination chemistry or applications. (SeeScheme 2.)

Condition: MeOH, R₂CHO (10 eqv), Refluxing, 48 hours.

Four different reactions were used in order to optimize the solutionphase parallel conditions (FIG. 1). These were optimized from differenttimes, temperatures, solvents, as well as balancing ratios ofdiamino-2-quinoxalinols (4) to substituted salicylaldehyde derivatives(5). In some cases, microwave heating or sonication was applied fordifficult reactions. According to previously preparations of Schiff basecompounds in the literature, methanol was selected as solvent, with aratio of 1:2.5 of diamino-2-quinoxalinol (4) to salicylaldehydederivative (5) at room temperature allowed to react for 48 hours. Underthese conditions the desired products were not obtained. Upon heatingfrom room temperature to reflux temperature the major product is thehalf-unit ligand 6cdh which has two possible structures and a smallamount of the full unit targeted compound 6cd; small amounts of products6ad and with a high yield only of 6ae. Whichever of the potentialisomeric products 6cdh is, there is another amino group which needs tobe reacted with the salicylaldehyde derivative. Hence, the exactstructure was not determined. The prolonging of reaction time from 48hours to 72 hours did not result in additional full unit products nordid increasing the reaction temperature benefit the reaction progress.Changing the solvent from methanol to higher boiling point solvents(e.g., toluene, DMF and benzene) allowed for increasing the refluxingtemperature, but did not produce the desired product. Both microwave andultrasonic methods also were tried, but without success.

Finally, on increasing the ratio of salicylaldehyde derivative from1:2.5 to 1:5 (FIG. 1), the yield of full unit target product went upfrom 20% to 31% for 6cd. The yields of 6ad and 6ac do not changedramatically. On increasing the ratio of to 1:7.5, the yields of targetproducts increased to 52% for 6ad, 44% for 6cd and 60% for 6ae. Thefinal products precipitated from methanol solution. This is useful forsolution phase parallel synthesis and allows for the use of parallelfiltration. When the ratio was increased from 1:7.5 to 1:10, the yieldof 6cd and 6ae increased to 57% and 77% but the yields for 6ad did notchange significantly. Continuing to increase the ratio did lead tobetter yields. The products were filtered directly resulting in yellowsolids. These were washed with 95% ethanol and cold acetone 5 timeseach. It was determined that there was no final product in the filteredsolution using TLC, and the yellow solids were pure full-unit ligandproducts. These were characterized by ¹H-NMR, ¹³C-NMR, MS and HRMS. Thepurity of 6ad, 6cd and 6ae identified by ¹H-NMR was no less than 99%.For 6da, at the ratio of 1:10 of 4d to 5a, the aim product 6da was notobtained, but when the reaction concentration was increased by reducingthe volume of solvent of methanol, under the ratio of 1:10, a relativelyhigh yields of 6da (65%) was obtained.

The final tested condition was a ratio of 1:0 (diamino-2-quinoxalinol tosalicylaldehyde derivative) which was reacted for 48 hours at refluxtemperature in a solution of methanol. When this was synthesized as a4×5 library, the procedure was found to be suitable for the solutionphase parallel synthesis of 2-quinoxalinol Schiff base ligands. Theresults are shown on Table 2, which illustrates that all of the twentytargeted products were synthesized by parallel methods with high yieldand purity.

TABLE 2 Synthesis results of 2-quinoxalinol Schiff base ligands library.No. Product R₁ R₂ Purity (%)^(†) Yield (%)^(¶) mp (° C.) 1 6aa

3-OH >90 50 251.0* 2 6ab

5-OH >95 41 246.0* 3 6ac

3-tert-butyl >95 55 271.0-273.5 4 6ad

3,5-Di-tert-butyl >99 56 279.1-280.1 5 6ae

H >99 77 264.1-266.1 6 6ba

3-OH >90 64 >300.0 7 6bb

5-OH >95 44 221.5* 8 6bc

3-tert-butyl >99 56 285.1-286.1 9 6bd

3,5-Di-tert-butyl >99 55 280.0-281.0 10 6be

H >90 70 288.5-289.3 11 6ca

3-OH >95 50 260.0-261.5 12 6cb

5-OH >90 67 290.5* 13 6cc

3-tert-butyl >95 52 285.1-286.7 14 6cd

3,5-Di-tert-butyl >99 57 287.8-288.8 15 6ce

H >99 86 286.5-288.5 16 6da

3-OH >90 65 >300.0 17 6db

5-OH >90 57 >300.0 18 6dc

3-tert-butyl >95 46 262.0* 19 6dd

3,5-Di-tert-butyl >99 56 286.0-287.5 20 6de

H >95 81 270.5* ^(†)Identified by the proportion of typical peak areasof ¹H-NMR, assuming the half unit Schiff base ligand is the only majorbyproduct. HPLC can not identify the exact percentage of this majorimpurity because the large difference of absorbance of their UV (254 or214 nm). ^(¶)Indicates a one-step yield from diamino-2-quinoxalinol 4 tofinal product 6. *At this temperature, these compounds were found todecompose.

Conclusion

A 2-quinoxalinol salen (or Schiff-base) ligand library was prepared byan efficient solution phase parallel method. It was found that theseorganic ligands are stable at high temperature (<200° C.) and notsensitive to oxygen, water, alkaline conditions or most solvents. In theprocess, the synthetic method for the key intermediate quinoxaline wasfurther optimized from methods used in previous reports.

From the resulting yields under the optimized conditions, some trendsare clear. With each quinoxaline, the yield of the product with aldehyde5e was significantly higher most likely due to limited steric hindrance,but yields were quite good with using aldehyde 5d, which should be themost sterically hindered aldehyde. This is also the aldehyde with thebest solubility and products from this aldehyde are soluble inchlorinated solvents, whereas some of the compounds synthesized fromaldehyde 5a and 5b are soluble only in DMSO. The most likely causes ofthe inhibition of product formation in reactions with aldehyde 5b arehydrogen bonding or an unfavorable transition state.

Experimental

All amino acid methyl esters, DFDNB, HCl (37%) and aldehydes werepurchased from Acros Organics Co. Ammonium hydroxide (5.0 N), palladiumon carbon (wet, 5%) were purchased from Sigma-Aldrich Co. Startingmaterials were used as received. All organic solvents were obtained fromThermo Fisher Scientific Co. and were directly used for synthesis. HPLCanalysis was performed on a Shimadzu™ apparatus equipped with a SPD-10AVP detector. Solutions for HPLC were eluted as 50/50 acetonitrile/H₂Owith a buffer consisting of 0.05% TFA over 10 min at 1 mL/min withdetection by UV at 254 rm. The column employed was a water C¹⁸ column(w33471F, 3.9×300 mm) from DIKMA Co. All melting points were recorded ona MeI-temp II melting point apparatus, and the values were uncorrected.¹H and ¹³C NMR spectra were recorded on Bruker™ AC 250 spectrometer(operated at 250 and 62.5 MHz, respectively) or Bruker™ AV 400spectrometer (operated at 400 and 100 MHz, respectively). Chemicalshifts are reported as 6 values (ppm). Some ¹H-NMR data were collectedusing DMSO-d⁶ and CDCl₃ to dissolve samples because they were notcompletely soluble only in DMSO-d⁶; however, if just CDCl₃ is used, theactive protons do not appear in D₂O/water exchange experiments. Thesolvents used are indicted in the experimental details. Reactionprogress was monitored by thin-layer chromatography (TLC) using 0.25 mmWhatman™ Aluminum silica gel 60-F254 precoated plates with visualizationby irradiation with a Mineralight™ UVGL-25 lamp. The parallel synthesiswas carried out on a Corning™ parallel synthesizer. Electrosprayionization mass spectrometry was performed on a Micromass QTOF™ massspectrometer (Waters Corp, Milford Mass.). Direct probe samples were ona VG-70S mass spectrometer (Waters Corp, Milford Mass.). All UV data wascollected using a Cary 50 UV-Vis spectrophotometer with a xenon lamp andan equipment range from 200 to 1250 nm. IR spectroscopic data wascollected using a Shimsdzu™ IR, Prestige-21 Fourier Transform InfraredSpectrophotometer and KBr solid samples. Samples for melting point, IR,and UV, were purified by recrystallization or -flash columnchromatography of the final 2-quinoxalinol products.

General Procedure

To a stirring solution of 150 mL of THF, 1.0 equivalent (10.0 mmol) of1,5-difluoro-2,4-dinitrobenzene (DFDNB), 2.2 equivalents (22 mmol) ofdiisopropylethylamine (DIPEA), and 1.0 equivalent methyl amino acid (10mmol) were added. The reaction mixture was stirred continuously for 12hours at room temperature. After it was confirmed by TLC that thestarting materials (DFDNB) had been consumed, 3 equiv (30 mmol) ofammonium hydroxide in water was added as 5.0N in aqueous solution to thereaction mixture. The reaction solution was stirred at room temperaturefor an additional 5 hours until the reaction was complete and this wasconfirmed by TLC. The reaction solution was concentrated to drynessusing a rotary evaporator resulting in a yellow oil or oily solid. Theresultant yellow oil was dissolved in 100 mL of ethanol (95%) withstirring. To this, HCOONH₄, 20 equiv., (0.2 mol) and 5% wet Pd—C (3.1 g,7.0 g for containing sulfur, catalytic) were added under a protective N₂atmosphere. The reaction mixture was heated to reflux temperature for15-30 minutes. During this time, the reaction mixture changed theinitial yellow to red and then to fluorescent yellow. After this time,the catalyst Pd—C and unreacted HCOONH₄ were filtered from the solution.The filtrate was put into freezer (0° C.) for 48-72 hours until yellowcrystals form. If there is no solids precipitate from the solution,sonication using an ultrasonic bath can help precipitate thediamino-2-quinoxalinols intermediate as a solid. Filtration of the solidfrom the reaction solution results in highly purediamino-2-quinoxalinols intermediate. The synthetic yield from startingmaterial of 4a, 4b, 4c and 4d were 60%, 59%, 58% and 41%, respectively.After drying on high vacuum, HPLC, ¹H-NMR and ¹³C-NMR show the purity ofeach of these are not less than 98%.

To 1.0 equiv (0.1 mmol) of the diamino-2-quinoxalinol intermediatedissolved in 4 mL methanol, a solution of 10.0 equiv (1 mmol) aldehydederivatives in 6 mL methanol was added. The two were combined withstirring, and after heating to reflux temperature for 1 hour, thereaction mixture becomes deep yellow or dark. After continued heating atreflux temperature for 48 hours, product forms and precipitates aseither dark yellow or red solids. The precipitate was filtered directlyand washed with 95% ethanol and cold acetone 5 times each to obtain the2-quinoxalinols Schiff base ligands as the final product. The yield offinal products ranges from 40% to 80% with the purity of them rangingfrom 90.0% to 99.0%. All of the final products were identified andcharacterized by ¹H-NMR, ¹³C-NMR, MS, HRMS, UV-Vis and IR.

For synthesis of 6aa, 6ca and 6 db, 1.0 equiv (0.1 mmol) ofdiamino-2-quinoxalinols intermediates was dissolved into 4 mL methanoland 10.0 equiv (1 mmol) aldehyde derivates was dissolved into 2 mLmethanol. Under stirring, mixer solution becomes red after refluxing 40min. After refluxing for 48 hours, a red precipitate formed. This wasfiltered directly and washed with 95% ethanol and cold acetone 5 timeseach to obtain product.

4a ¹H-NMR (400 MHz DMSO-d⁶): δ 3.99 (s, 2H), 4.66 (bs, 2H), 5.47 (bs,2H), 6.37 (s, 1H), 6.80 (s, 1H), 7.16-7.31 (m, 5H), 11.86 (bs, 1H).¹³C-NMR (100 MHz, DMSO-d⁶): 6155.1, 152.2, 140.5, 139.4, 133.0, 129.4,128.6, 126.4, 125.8, 111.0, 96.8, 38.8. Formula: C₁₅H₁₄N₄O. MS (M+H):267.0. HRMS: found (267.1256), calc (267.1246). IR: 3172.9 cm⁻¹ (bs),3381.2 cm⁻¹ (bs), 3182.6 cm⁻¹ (bs), 3005.2 cm⁻¹, 1645.3 cm⁻¹, 1510.3cm⁻¹, 1402.3 cm⁻¹, 1278.8 cm⁻¹. UV: 402.9 nm (bs).

4b ¹H-NMR (400 MHz DMSO-d⁶): δ 1.13 (d, J=6.8, 6H), 3.33 (sept, 1H),4.66 (bs, 2H), 5.36 (bs, 2H), 6.33 (s, 1H), 6.78 (s, 1H), 11.73 (bs,1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 157.7, 154.7, 140.1, 132.8, 125.9,125.5, 111.3, 96.9, 29.7, 21.0. Formula: C₁₁H₁₄N₄O. MS (M+H): 219.0.HRMS: found (219.1248), calc (219.1246). IR: 3381.2 cm⁻¹ (bs), 3365.1cm⁻¹ (bs), 2962.7 cm⁻¹, 2929.9 cm⁻¹, 1656.9 cm⁻¹, 1512.2 cm⁻¹, 1406.1cm⁻¹, 1273.0 cm⁻¹. UV: 394.0 nm (bs).

4c ¹H-NMR (250 MHz DMSO-d⁶): δ 0.90 (d, J=6.7, 6H), 2.15 (m, 1H), 2.50(d, 2H), 4.62 (bs, 2H), 5.39 (bs, 2H), 6.35 (s, 1H), 6.79 (s, 1H), 11.98(bs, 1H). ¹³C-NMR (62.5 MHz, DMSO-d⁶): δ 155.4, 153.2, 140.1, 132.8,126.0, 125.8, 111.2, 96.9, 41.7, 26.9, 23.0. Formula: C₁₂H₁₆N₄O. MS(M+H): 233.0. HRMS: found (233.1410), calc (233.1402). IR: 3352.3cm⁻¹(bs), 3277.1 cm⁻¹ (bs), 2949.2 cm⁻¹, 2868.2 cm⁻¹, 2818.0 cm⁻¹,1653.0 cm⁻¹, 1512.2 cm⁻¹, 1419.6 cm⁻¹, 1402.3 cm⁻¹, 1271.1 cm⁻¹. UV:410.6 nm (bs), 299.1 (wbs). 4d ¹H-NMR (400 MHz DMSO-d⁶): δ 2.09 (s, 3H),2.83 (t, 2H), 2.95 (t, 2H), 5.19 (bs, 2H), 5.65 (bs, 2H), 6.39 (s, 1H),6.82 (s, 1H), 11.99 (bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 155.2,151.8, 140.4, 132.9, 126.2, 125.8, 111.1, 96.9, 32.9, 31.1, 15.1.Formula: C₁₁H₁₄N₄OS. MS (M+H): 251.0. HRMS: found (251.0966), calc(251.0963). IR: 3321.4 cm⁻¹(bs), 3219.2 cm⁻¹(bs), 2920.2 cm⁻¹, 2879.7cm⁻¹, 1643.4 cm⁻¹, 1510.3 cm⁻¹, 1402.3 cm⁻¹, 1273.0 cm⁻¹. UV: 391.0 nm(bs).

6aa ¹H-NMR (400 MHz DMSO-d⁶): δ 4.14 (s, 2H), 6.77-7.34 (m, 12H), 7.87(s, 1H), 8.83 (s, 1H), 9.04 (s, 1H), 9.22 (bs, 1H, D₂O exchangeable),9.41 (bs, 1H, D₂O exchangeable), 12.18 (bs, 1H, D₂O exchangeable), 12.53(bs, 1H, D₂O exchangeable), 12.99 (bs, 1H, D₂O exchangeable). ¹³C-NMR(100 MHz, DMSO-d⁶): δ 165.6, 164.8, 160.7, 154.9, 150.0, 149.7, 146.2,146.1, 145.7, 138.2, 137.9, 132.1, 129.7, 128.8, 126.9, 123.4, 122.9,120.3, 120.2, 119.8, 119.6, 118.4, 106.0, 40.0. Formula: C₂₉H₂₂N₄O₅. MS:507.0. HRMS: found (507.1666), calc (507.1668). IR: 3392.8 cm⁻¹(bs),3005.2 cm⁻¹, 1656.8 cm⁻¹, 1616.3 cm⁻¹, 1467.8 cm⁻¹, 1271.1 cm⁻¹, 1234.4cm⁻¹. UV: 383.0 nm (bs).

6ab ¹H-NMR (400 MHz DMSO-d⁶): δ 4.14 (s, 2H), 6.74-7.35 (m, 12H), 7.87(s, 1H), 8.74 (s, 1H), 8.97 (s, 1H), 9.08 (bs, 1H, D₂O exchangeable),9.12 (bs, 1H, D₂O exchangeable), 11.43 (bs, 1H, D₂O exchangeable), 12.31(bs, 1H, D₂O exchangeable), 12.50 (bs, 1H, D₂O exchangeable). ¹³C-NMR(100 MHz, DMSO-d⁶): δ 164.3, 163.8, 160.6, 155.0, 153.8, 153.5, 150.2,150.0, 146.5, 138.0, 137.9, 132.1, 131.1, 129.7, 128.9, 126.9, 122.4,121.7, 120.2, 119.9, 118.1, 117.9, 117.7, 117.5, 116.5, 105.9, 40.0.Formula: C₂₉H₂₂N₄O₅. MS (M+H): 507.0. HRMS: found (507.1667), calc(507.1668). IR: 3387.0 cm⁻¹(bs), 3005.0 cm⁻¹, 1662.6 cm⁻¹, 1616.4 cm⁻¹,1573.9 cm⁻¹, 1487.1 cm⁻¹, 1282.7 cm⁻¹, 1153.4 cm⁻¹. UV: 378.0 nm (bs).

6ac ¹H-NMR (400 MHz DMSO-d⁶): δ 1.31 (s, 9H), 1.34 (s, 9H), 4.15 (s,2H), 6.77-7.44 (m, 12H), 7.62 (s, 1H), 8.58 (s, 1H), 8.70 (s, 1H), 12.26(bs, 1H), 13.42 (bs, 1H), 13.60 (bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ165.4, 163.7, 160.6, 160.4, 155.1, 144.6, 138.4, 137.7, 137.4, 137.0,133.9, 131.9, 131.7, 130.7, 129.3, 128.2, 126.4, 126.1, 119.2, 118.9,118.7, 118.2, 117.9, 105.5, 34.7, 29.2. Formula: C₃₇H₃₈N₄O₃. MS (M+H):587.0. HRMS: found (587.3028), calc (587.3022). IR: 3437.2 cm⁻¹(bs),3417.9 cm⁻¹(bs), 2953.0 cm⁻¹, 2912.5 cm⁻¹, 1672.3 cm⁻¹, 1606.7 cm⁻¹,1500.6 cm⁻¹, 1431.2 cm⁻¹, 1394.5 cm⁻¹, 1197.8 cm⁻¹, 1143.8 cm⁻¹. UV:285.7 nm (bs), 387.9 nm (bs).

6ad ¹H-NMR (250 MHz DMSO-d⁶ and CDCl₃): δ 1.23 (s, 18H), 1.32 (s, 9H),1.34 (s, 9H), 4.14 (s, 2H), 7.01 (s, 1H), 7.12-7.41 (m, 9H), 7.59 (s,1H), 8.58 (s, 1H), 8.68 (s, 1H), 12.22 (bs, 1H), 13.25 (bs, 1H), 13.36(bs, 1H). ¹³C-NMR (62.5 MHz, DMSO-d⁶ and CDCl₃): δ 165.9, 164.3, 160.2,158.6, 158.3, 155.3, 144.9, 140.6, 140.5, 138.9, 137.2, 137.1, 136.9,131.7, 131.5, 129.5, 128.7, 128.4, 128.2, 127.2, 127.0, 126.5, 118.4,118.1, 118.1, 105.6, 35.1, 34.1, 31.5, 29.4. Formula: C₄₅H₅₄N₄O₃ MS(M+H): 699.0. HRMS: found (699.4276), calc (699.4274). IR: 3435.2cm⁻¹(bs), 3415.9 cm⁻¹(bs), 2956.9 cm⁻¹, 2910.6 cm⁻¹, 2873.9 cm⁻¹, 1656.9cm⁻¹, 1612.5 cm⁻¹, 1529.6 cm⁻¹, 1477.5 cm⁻¹, 1442.8 cm⁻¹, 1261.5 cm⁻¹,1168.9 cm⁻¹. UV: 299.1 nm (bs), 390.9 nm (bs).

6ae ¹H-NMR (400 MHz DMSO-d⁶): δ 4.17 (s, 2H), 6.95-7.03 (m, 2H), 7.11(s, 1H), 7.25-7.49 (m, 7H), 7.66 (d, 11H), 7.79 (d, 11H), 7.94 (s, 11H),8.90 (s, 11H), 9.13 (s, 11H), 12.28 (bs, 1H), 12.57 (bs, 1H), 13.13 (bs,1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 164.6, 164.0, 160.9, 160.8, 160.6,155.0, 146.0, 138.1, 137.9, 134.5, 133.8, 133.1, 132.3, 132.2, 131.2,129.8, 128.9, 126.9, 120.2, 120.0, 119.9, 119.6, 118.1, 117.2, 117.1,105.8, 40.0. Formula: C₂₉H₂₂N₄O₃ MS (M+H): 475.0. HRMS: found(475.1762), calc (475.1770). IR: 3448.7 cm⁻¹(bs), 3427.5 cm⁻¹(bs),3055.2 cm⁻¹, 3030.2 cm⁻¹, 1654.9 cm⁻¹, 1610.6 cm⁻¹, 1570.1 cm⁻¹, 1481.3cm⁻¹, 1276.9 cm⁻¹, 1197.8 cm⁻¹. UV: 305.6 nm (wbs), 335.9 nm (wbs),390.5 nm (bs).

6ba ¹H-NMR (400 MHz DMSO-d⁶): , 1.26 (d, J=6.8 Hz, 6H), 3.50 (sept,11H), 6.80 (t, 1H), 6.84 (t, 1H), 6.94 (d, 1H), 6.99 (d, 1H), 7.01 (s,1H), 7.14 (d, 1H), 7.22 (d, 1H), 7.92 (s, 1H), 8.87 (s, 1H), 9.11 (s,1H), 9.24 (bs, 1H), 9.43 (bs, 1H), 12.24 (bs, 1H), 12.48 (bs, 1H), 13.06(bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 166.0, 165.6, 164.8, 154.6,150.0, 149.7, 146.2, 146.1, 145.4, 138.1, 131.8, 131.1, 123.5, 122.9,120.3, 120.2, 120.0, 119.6, 119.2, 118.3, 106.0, 30.4, 20.6. Formula:C₂₅H₂₂N₄O₅. MS (M+H): 459.0. HRMS: found (459.1675), calc (459.1668).IR: 3421.7 cm⁻¹(bs), 3059.1 cm⁻¹, 2966.5 cm⁻¹, 2926.0 cm⁻¹, 1656.9 cm⁻¹,1616.4 cm⁻¹, 1556.6 cm⁻¹, 1465.9 cm⁻¹, 1373.3 cm⁻¹, 1273.0 cm⁻¹, 1230.6cm⁻¹. UV: 306.5 nm (bs), 389.6 nm (bs).

6bb ¹H-NMR (400 MHz DMSO-d⁶): δ 1.23 (d, J=6.8 Hz, 6H), 3.48 (sept, 1H),6.74-7.12 (m, 7H), 7.88 (s, 11H), 8.74 (s, 11H), 9.01 (s, 1H), 9.08 (bs,1H, D₂O exchangeable), 9.13 (bs, 1H, D₂O exchangeable), 11.46 (bs, 1H,D₂O exchangeable), 12.36 (bs, 1H, D₂O exchangeable), 12.42 (bs, 1H, D₂Oexchangeable). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 165.9, 164.3, 163.8, 154.6,153.8, 153.5, 150.2, 150.0, 146.2, 138.2, 131.8, 130.9, 122.3, 121.7,120.2, 120.0, 118.0, 117.9, 117.6, 116.5, 105.8, 30.4, 20.6. Formula:C₂₅H₂₂N₄O₅. MS (M+H): 458.0. HRMS: found (459.1665), calc (459.1668).IR: 3400.5 cm⁻¹(bs), 2962.7 cm⁻¹, 2926.0 cm⁻¹, 1656.9 cm⁻¹, 1627.9 cm⁻¹,1579.7 cm⁻¹, 1490.8 cm⁻¹, 1400.0 cm⁻¹, 1273.0 cm⁻¹, 1219.0 cm⁻¹. UV:299.1 nm (bs), 387.0 nm (bs).

6bc ¹H-NMR (400 MHz DMSO-d⁶): δ 1.27 (d, J=6.8 Hz, 6H), 1.37 (s, 9H),1.42 (s, 9H), 3.52 (sept, 1H), 6.93 (t, 1H), 6.95 (t, 1H), 7.20 (s, 1H),7.38 (d, 1H), 7.44 (d, 1H), 7.54-7.58 (t, 2H), 8.00 (s, 1H), 8.94 (s,1H), 9.19 (s, 1H), 12.51 (bs, 1H), 13.73 (bs, 1H), 14.04 (bs, 1H).¹³C-NMR (100 MHz, DMSO-d⁶): δ 167.1, 166.3, 165.5, 160.5, 160.4, 154.6,144.5, 137.9, 137.6, 137.1, 137.0, 132.2, 132.0, 131.4, 131.3, 130.8,119.7, 119.4, 119.1, 118.9, 118.3, 105.9, 34.9, 30.4, 29.7, 20.6.Formula: C₃₃H₃₈N₄O₃ MS (M+H): 539.0. HRMS: found (539.3024), calc(539.3022). IR: 3429.4 cm⁻¹(bs), 2956.9 cm⁻¹, 2872.0 cm⁻¹, 1660.7 cm⁻¹,1606.7 cm⁻¹, 1467.8 cm⁻¹, 1431.2 cm⁻¹, 1388.8 cm⁻¹, 1270.0 cm⁻¹, 1199.7cm⁻¹. UV: 302.2 nm (bs), 386.2 nm (bs).

6bd ¹H-NMR (400 MHz DMSO-d⁶ and CDCl₃): δ 1.20 (s, 9H), 1.21 (s, 9H),1.21 (d, J=6.8 Hz, 6H), 1.29 (s, 9H), 1.32 (s, 9H), 3.52 (sept, 1H),6.99 (s, 1H), 7.17 (s, 2H), 7.34 (s, 1H), 7.37 (s, 1H), 7.62 (s, 1H),8.59 (s, 1H), 8.72 (s, 1H), 12.12 (bs, 1H), 13.28 (bs, 1H), 13.39 (bs,1H). ¹³C-NMR (100 MHz, DMSO-d⁶ and CDCl₃): 165.9, 165.7, 164.1, 158.5,158.3, 155.1, 144.5, 140.5, 140.4, 138.8, 137.1, 136.9, 131.5, 131.2,128.6, 128.1, 127.1, 126.8, 118.3, 118.1, 118.0, 105.4, 35.0, 34.1,31.4, 30.3, 29.3, 20.1. Formula: C₄₁H₅₄N₄O₃. MS (M+H): 651.0. HRMS:found (651.4274), calc (651.4268). IR: 3423.7 cm⁻¹(bs), 2958.8 cm⁻¹,2910.6 cm⁻¹, 2870.1 cm⁻¹, 1653.0 cm⁻¹, 1614.4 cm⁻¹, 1581.6 cm⁻¹, 1469.8cm⁻¹, 1437.0 cm⁻¹, 1390.7 cm⁻¹, 1363.7 cm⁻¹, 1253.7 cm⁻¹, 1203.6 cm⁻¹.UV: 299.6 nm (bs), 387.9 nm (bs).

6be H-NMR (400 MHz DMSO-d⁶): δ 1.23 (d, J=6.8 Hz, 6H), 3.47 (sept, 1H),6.91-7.00 (m, 4H), 7.08 (s, 1H), 7.39 (t, 1H), 7.44 (t, 1H), 7.66 (d,1H), 7.76 (d, 1H), 7.93 (s, 1H), 8.87 (s, 1H), 9.15 (s, 1H), 12.28 (bs,1H), 12.46 (bs, 1H), 13.14 (bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ166.1, 164.6, 163.9, 160.9, 160.6, 154.6, 145.7, 137.9, 134.4, 133.8,133.1, 132.4, 132.0, 131.1, 120.2, 119.8, 119.5, 118.1, 117.2, 117.1,105.7, 30.4, 20.6. Formula: C₂₅H₂₂N₄O₃. MS (M+H): 427.0. HRMS: found(427.1764), calc (427.1770). IR: 3441.0 cm⁻¹(bs), 2964.6 cm⁻¹, 2924.1cm⁻¹, 1658.8 cm⁻¹, 1616.4 cm⁻¹, 1570.1 cm⁻¹, 1479.4 cm⁻¹, 1452.0 cm⁻¹,1278.8 cm⁻¹, 1203.6 cm⁻¹. UV: 335.9 nm (bs), 387.9 nm (bs).

6ca ¹H-NMR (400 MHz DMSO-d⁶): δ 1.23 (d, J=6.6 Hz, 6H), 2.27 (m, 1H),2.71 (d, J=7.0, 2H), 6.80 (t, 1H), 6.83 (t, 1H), 6.95 (d, 1H), 7.00 (d,1H), 7.09 (s, 1H), 7.14 (t, 2H), 7.22 (t, 2H), 7.92 (s, 1H), 8.87 (s,1H), 9.08 (s, 1H), 9.24 (bs, 1H, D₂O exchangeable), 9.42 (bs, 1H, D₂Oexchangeable), 12.25 (bs, 1H, D₂O exchangeable), 12.47 (bs, 1H, D₂Oexchangeable), 13.04 (bs, 1H, D₂O exchangeable). ¹³C-NMR (100 MHz,DMSO-d⁶): δ 165.6, 164.7, 161.7, 155.2, 150.0, 149.7, 146.2, 146.1,145.4, 138.1, 131.9, 131.2, 123.4, 122.9, 120.3, 120.2, 120.0, 119.6,119.2, 118.3, 106.0, 42.1, 26.6, 23.1. Formula: C₂₆H₂₄N₄O₅. MS (M+H):473.0. HRMS: found (473.1818), calc (473.1825). IR: 3419.8 cm⁻¹(bs),2949.2 cm⁻¹, 2866.2 cm⁻¹, 1656.9 cm⁻¹, 1618.3 cm⁻¹, 1579.7 cm⁻¹, 1465.9cm⁻¹, 1373.3 cm⁻¹, 1271.1 cm⁻¹, 1232.5 cm⁻¹. UV: 301.3 nm (bs), 381.0 nm(bs).

6cb ¹H-NMR (400 MHz DMSO-d⁶): δ 0.98 (d, J=6.6 Hz, 6H), 2.27 (m, 1H),2.71 (d, J=7.0, 2H), 6.77-6.91 (m, 4H), 7.06 (s, 2H), 7.14 (s, 1H), 7.92(s, 1H), 8.77 (s, 1H), 9.01 (s, 1H), 9.12 (bs, 1H), 9.15 (bs, 1H), 11.49(bs, 1H), 12.36 (bs, 1H), 12.45 (bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ164.4, 163.7, 161.5, 155.2, 153.8, 153.5, 150.2, 150.0, 146.2, 138.2,131.9, 131.1, 120.2, 119.9, 117.9, 117.6, 117.5, 116.5, 105.8, 42.1,26.7, 23.1. Formula: C₂₆H₂₄N₄O₅. MS (M+H): 473.0. HRMS: found(473.1832), calc (473.1825). IR: 3427.5 cm⁻¹ (bs), 3412.1 cm⁻¹(bs),2956.9 cm⁻¹, 2924.1 cm⁻¹, 1658.8 cm⁻¹, 1618.3 cm⁻¹, 1577.8 cm⁻¹, 1483.3cm⁻¹, 1379.1 cm⁻¹, 1286.5 cm⁻¹, 1213.2 cm⁻¹. UV: 303.9 nm (bs), 395.7 nm(bs).

6 cc ¹H-NMR (400 MHz DMSO-d₆): δ 0.99 (d, J=6.6 Hz, 6H), 13.7 (s, 9H),1.42 (s, 9H), 2.29 (m, 1H), 2.72 (d, J=7.0, 2H), 6.93 (t, 1H), 6.95 (t,1H), 7.20 (s, 1H), 7.38 (d, 1H), 7.44 (d, 1H), 7.53-7.58 (m, 2H), 8.01(s, 1H), 8.93 (s, 1H), 9.16 (s, 1H), 12.51 (bs, 1H), 13.73 (bs, 1H),14.03 (bs, 1H). ¹³C-NMR (100 MHz, DMSO-d₆): δ 167.1, 165.5, 161.9,160.5, 160.4, 155.2, 144.5, 137.9, 137.2, 137.0, 132.2, 132.0, 131.9,131.4, 130.8, 119.7, 119.4, 119.1, 118.9, 118.2, 105.9, 42.1, 34.9,29.7, 26.6, 23.1. Formula: C₃₄H₄₀N₄O₃ MS (M+H): 553.0. HRMS: found(553.3177), calc (553.3178). IR: 3423.7 cm⁻¹(bs), 2955.0 cm⁻¹, 2918.3cm⁻¹, 2870.1 cm⁻¹, 1662.6 cm⁻¹, 1604.8 cm⁻¹, 1573.9 cm⁻¹, 1496.8 cm⁻¹,1469.8 cm⁻¹, 1431.2 cm⁻¹, 1396.5 cm⁻¹, 1273.0 cm⁻¹, 1199.7 cm⁻¹. UV:299.6 nm (bs), 382.7 nm (bs).

6cd ¹H-NMR (250 MHz DMSO-d⁶ and CDCl₃): δ 0.82 (d, J=6.6 Hz, 6H), 1.10(s, 9H), 1.11 (s, 9H), 1.19 (s, 9H), 1.22 (s, 9H), 2.13 (m, 1H), 2.57(d, J=7.1, 2H), 6.88 (s, 1H), 7.04-7.06 (dd, 2H), 7.21 (d, 2H), 7.23 (d,2H), 7.47 (s, 1H), 8.47 (s, 1H), 8.58 (s, 1H), 12.08 (bs, 1H), 13.15(bs, 1H), 13.25 (bs, 1H). ¹³C-NMR (62.5 MHz, DMSO-d⁶ and CDCl₃): δ166.6, 164.1, 161.4, 158.4, 158.1, 155.6, 144.4, 140.4, 138.7, 136.9,136.8, 131.3, 128.5, 128.0, 127.0, 126.8, 118.2, 118.0, 117.8, 105.4,42.0, 34.9, 34.0, 31.3, 29.3, 26.5, 22.6. Formula: C₄₂H₅₆N₄O₃ MS (M+H):665.0. HRMS: found (665.4431), calc (665.4430). IR: 3423.7 cm⁻¹(bs),2956.9 cm⁻¹, 2920.1 cm⁻¹, 2880.1 cm⁻¹, 1656.9 cm⁻¹, 1616.4 cm⁻¹, 1583.6cm⁻¹, 1469.8 cm⁻¹, 1437.0 cm⁻¹, 1386.8 cm⁻¹, 1367.5 cm⁻¹, 1255.7 cm⁻¹,1207.4 cm⁻¹. UV: 301.3 nm (bs), 389.6 nm (bs).

6ce ¹H-NMR (250 MHz DMSO-d⁶): δ 0.98 (d, J=6.5 Hz, 6H), 2.27 (m, 1H),2.70 (d, J=6.9, 2H), 6.94-7.11 (m, 4H), 7.38 (s, 1H), 7.41-7.46 (m, 2H),7.68 (d, 1H), 7.79 (d, 1H), 7.96 (s, 1H), 8.89 (s, 1H), 9.14 (s, 1H),12.34 (bs, 2H), 13.14 (bs, 1H). ¹³C-NMR (62.5 MHz, DMSO-d⁶): δ 164.6,163.9, 161.7, 160.9, 160.6, 155.2, 145.6, 138.0, 134.4, 133.8, 133.1,132.4, 132.0, 131.2, 120.2, 120.0, 119.8, 119.5, 118.0, 117.2, 105.8,42.1, 26.6, 23.1. Formula: C₂₆H₂₄N₄O₃. MS (M+H): 441.0. HRMS: found(441.1922), calc (441.1926). IR: 3441.0 cm⁻¹(bs), 3425.6 cm⁻¹(bs),2955.0 cm⁻¹, 2922.2 cm⁻¹, 2864.3 cm⁻¹, 1658.8 cm⁻¹, 1616.4 cm⁻¹ 1572.0cm⁻¹, 1485.2 cm⁻¹, 1384.9 cm⁻¹, 1278.8 cm⁻¹, 1203.6 cm⁻¹. UV: 383.6 nm(bs).

6da ¹H-NMR (400 MHz DMSO-d⁶): δ 2.14 (s, 3H), 2.95 (t, 2H), 3.13 (t,2H), 6.81 (t, 1H), 6.84 (t, 1H), 6.95 (d, 1H), 7.00 (d, 1H), 7.11 (s,1H), 7.15 (d, 1H), 7.23 (d, 1H), 7.92 (s, 1H), 8.88 (s, 1H), 9.08 (s,1H), 9.25 (bs, 1H, D₂O exchangeable), 9.43 (bs, 1H, D₂O exchangeable),12.23 (bs, 1H, D₂O exchangeable), 12.53 (bs, 1H, D₂O exchangeable),13.02 (bs, 1H, D₂O exchangeable). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 165.7,164.8, 160.6, 155.0, 149.9, 149.7, 146.2, 146.1, 145.6, 138.2, 132.0,131.1, 123.4, 122.9, 120.3, 120.2, 120.0, 119.6, 119.2, 118.3, 106.1,33.2, 30.5, 15.0. Formula: C₂₅H₂₂N₄O₅S. MS (Mt-+H): 491.0. HRMS: found(491.1389), calc (491.1389). IR: 3415.9 cm⁻¹(bs), 2920.2 cm⁻¹, 2852.7cm⁻¹, 1656.9 cm⁻¹, 1616.4 cm⁻, 1467.8 cm⁻¹, 1373.3 cm⁻¹, 1271.1 cm⁻¹,1230.6 cm⁻¹. UV: 307.4 nm (bs), 390.5 nm (bs).

6db ¹H-NMR (400 MHz DMSO-d⁶): δ 2.14 (s, 3H), 2.94 (t, 2H), 3.12 (t,2H), 6.77-6.93 (m, 4H), 7.06 (s, 2H), 7.14 (s, 1H), 7.92 (s, 1H), 8.78(s, 1H), 8.80 (s, 1H), 9.12 (bs, 1H), 9.16 (bs, 1H), 11.48 (bs, 1H),12.34 (bs, 1H), 12.49 (bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 164.4,163.8, 153.8, 153.5, 150.2, 150.0, 132.0, 121.7, 120.2, 119.9, 118.1,117.9, 117.7, 116.5, 105.9, 33.1, 30.1, 15.2. Formula: C₂₅H₂₂N₄O₅S MS(M+H): 491.0. HRMS: found (491.1384), calc (491.1389). IR: 3439.1cm⁻¹(bs), 2972.3 cm⁻¹, 2924.1 cm⁻¹, 1654.9 cm⁻¹, 1624.1 cm⁻¹, 1575.8cm⁻¹, 1477.5 cm⁻¹, 1388.8 cm⁻¹, 1282.7 cm⁻¹, 1220.9 cm⁻¹. UV: 302.2 nm(wbs), 391.4 nm (bs).

6dc ¹H-NMR (250 MHz DMSO-d⁶): δ 1.36 (s, 9H), 1.40 (s, 9H), 2.14 (s,3H), 2.94 (t, 2H), 3.11 (t, 2H), 6.93-6.98 (m, 2H), 7.20 (s, 1H), 7.39(d, 1H), 7.41 (d, 1H), 7.54 (t, 2H), 8.00 (s, 1H), 8.93 (s, 1H), 9.14(s, 1H), 12.56 (bs, 1H), 13.72 (bs, 1H), 14.01 (bs, 1H). ¹³C-NMR (62.5MHz, DMSO-d⁶): δ 166.9, 165.2, 160.6, 160.4, 154.9, 144.6, 138.1, 137.2,137.0, 132.1, 131.8, 131.3, 130.6, 119.6, 119.3, 118.9, 118.7, 118.2,105.9, 34.9, 33.2, 30.5, 29.6, 15.3. Formula: C₃₃H₃₈N₄O₃S MS (M+H):571.0. HRMS: found (571.2738), calc (571.2743). IR: 3433.3 cm⁻¹(bs),3417.9 cm⁻¹(bs), 2953.0 cm⁻¹, 2920.2 cm⁻¹, 2872.0 cm⁻¹, 1666.5 cm⁻¹,1654.9 cm⁻¹, 1606.7 cm⁻¹, 1489.1 cm⁻¹, 1427.3 cm⁻¹, 1388.8 cm⁻¹, 1311.6cm⁻¹, 1267.2 cm⁻¹. UV: 305.6 nm (bs), 389.6 nm (bs).

6dd ¹H-NMR (400 MHz DMSO-d⁶ and CDCl₃): δ 1.20 (s, 9H), 1.21 (s, 9H),1.29 (s, 9H), 1.32 (s, 9H), 2.15 (s, 3H), 2.90 (t, 2H), 3.12 (t, 2H),6.97 (s, 1H), 7.14 (s, 2H), 7.31 (d, 1H), 7.34 (d, 1H), 7.56 (s, 1H),8.55 (s, 1H), 8.65 (s, 1H), 12.20 (bs, 1H), 13.21 (bs, 1H), 13.32 (bs,1H). ¹³C-NMR (100 MHz, DMSO-d⁶ and CDCl₃): δ 165.8, 164.3, 159.8, 158.6,158.3, 155.4, 144.9, 140.5, 140.4, 139.0, 137.1, 137.0, 131.4, 131.3,128.7, 128.2, 127.1, 126.9, 118.3, 118.1, 118.0, 105.6, 35.0, 34.1,33.1, 31.4, 30.6, 29.3, 15.5. Formula: C₄₁H₅₄N₄O₃S MS (M+H): 683.0.HRMS: found (683.4005), calc (683.3995). IR: 3441.0 cm⁻¹(bs), 3425.6cm⁻¹(bs), 2956.9 cm⁻¹, 2914.4 cm⁻¹, 2870.1 cm⁻¹, 1656.9 cm⁻¹, 1616.4cm⁻¹, 1583.6 cm⁻¹, 1469.8 cm⁻¹, 1433.1 cm⁻¹, 1386.8 cm⁻¹, 1269.2 cm⁻¹,1259.5 cm⁻¹. UV: 302.2 nm (bs), 391.4 nm (bs).

6de ¹H-NMR (400 MHz DMSO-d⁶): δ 2.14 (s, 3H), 2.95 (t, 2H), 3.13 (t,2H), 6.95-7.04 (m, 4H), 7.12 (s, 1H), 7.42 (t, 1H), 7.47 (t, 1H), 7.70(d, 1H), 7.79 (d, 1H), 7.96 (s, 1H), 8.91 (s, 1H), 9.14 (s, 1H), 12.30(bs, 1H), 12.54 (bs, 1H), 13.12 (bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ164.7, 164.0, 160.9, 160.6, 155.0, 145.8, 138.1, 134.5, 133.8, 133.1,120.2, 120.0, 119.9, 118.1, 117.2, 117.1, 105.8, 33.2, 30.5, 15.2.Formula: C₂₅H₂₂N₄O₃S MS (M+H): 459.0. HRMS: found (459.1489), calc(459.1491). IR: 3441.0 cm⁻¹(bs), 3423.6 cm⁻¹(bs), 2916.4 cm⁻¹, 2841.2cm⁻¹, 2796.8 cm⁻¹, 1660.7 cm⁻¹, 1614.4 cm⁻¹, 1570.1 cm⁻¹, 1479.4 cm⁻¹,1398.4 cm⁻¹, 1276.9 cm⁻¹, 1201.6 cm⁻¹. UV: 335.9 nm (bs), 387.0 nm (bs).

Example 1 References

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Example 2

Reference is made to Wu et al., “Regioselective Synthesis ofAsymmetrically Substituted 2-Quinoxalinol Salen Ligands,” J. Org. Chem.,November 9; 72(23):8691-9. Epub 2007 Oct. 16., the content of which isincorporated herein by reference in its entirety.

Abstract and Introduction

Diamino-2-quinoxalinols were reacted with salicylaldehyde derivatives toproduce 2-quinoxalinol imines regioselectively as one isomer in goodyield. Regioselectivity was characterized through the use of isotopic¹⁵N labeling experiments. The 2-quinoxalinol imines thereby obtained mayfurther be reacted without purification with additional salicylaldehydederivatives to yield asymmetrically substituted 2-quinoxalinol salens.

The synthesis of 2-quinoxalinol imines is challenging, because they areoften unstable, particularly when using bulky imines. The synthesis ofthe key intermediate, the 2-quinoxalinol imine (3a) fromdiamino-2-quinoxalinol (1) is a unique challenge, because of thedifficulty in obtaining one isomer as the final product. If the reactioncan be controlled such that only one amine is reacted with an aldehyde,this would provide a method to develop asymmetrically substituted2-quinoxalinol salens. Here, a side product determined to be the halfunit salen ligand, that is, a single product, a 2-quinoxalinol imine (3)was successfully synthesized and isolated. The use of this side productas a starting material for asymmetrically substituted ligands provides ameans to overcome the difficulty of synthesis in producingregioselective or bulky 2-quinoxalinol imine compounds. In addition,these 2-quinoxalinol imines are stable in atmospheric conditions.

Scheme 3 illustrates that identifying the exact structure of the2-quinoxalinol imines is difficult because two isomers [(3a) or (3b)]are possible.

Here, the exact structure of these 2-quinoxalinol imine was determinedusing isotope ¹⁵N labeled compounds and NMR technology. The reaction wasfound to be regioselective. Based on these observations, several2-quinoxalinol imine intermediates were synthesized and used assynthetic building blocks in the preparation of asymmetricallysubstituted salen-based ligands.

Results and Discussion

The general synthetic route for the formation of the 2-quinoxalinolsalen ligands has been reported previously, and it was previously shownthat the ratio of the starting materials used (diamino-2-quinoxalinol(1) to salicylaldehyde derivatives (2)) is important for optimization ofthe reaction. When the ratio is 1:1.2, a 2-quinoxalinol imine is themajor product with high regioselectivity. If the ratio of reactants isincreased, the yield of symmetric 2-quinoxalinol salens increases. Asthe ratio of reactants reaches 1:10, the yield of the symmetric2-quinoxolinol salen is much higher.

The identification of 2-quinoxalinol imine intermediates in the reactionis important to determine the utility of these compounds in asymmetricsyntheses, because two configurations [(3a) or (3b)] are possible. Inorder to identify the exact structure, the two amino groups of thediamino-2-quinoxalinol intermediate (1) were differentiated by replacingammonium hydroxide with ¹⁵N labeled ammonium hydroxide during thesecondary substitution of the 1,5-difluoro-2,4-dinitrobenzene (DFDNB).Because of the heteronuclear coupling of ¹⁵N, ¹H-NMR can be used todemonstrate a difference between the two amino groups of intermediate(1). Thus, in the 2-quinoxalinol imine intermediate, the position of theimine formation (whether on the ¹⁵N or 14N of intermediate (1)) can beidentified. The ¹H-NMR spectra with intermediate (1a), 2-quinoxalinolimine (3ae) and the ¹⁵N labeled intermediate (1a), 2-quinoxalinol imine(3ae) are shown in FIG. 2.

In FIG. 2, for intermediate (1a), the “a” labeled peaks corresponding tothe two protons of the ¹⁴N and ¹⁵N amino groups are different in spectraI and II. Spectra I has a broad single peak, while in spectra II, with¹⁵N heteronulear coupling, the protons are split (J=78.0 Hz). For the¹⁵N labeling 2-quinoxalinol imines (3ae-¹⁵N), the peak marked “b”corresponding to the proton on the carbon of imine group are split by¹⁵N (J=3.0) (spectra IV), whereas it is still a single peak in spectraIII. At the same time, in the spectra III and IV, the peak (δ=4.66 ppm)disappear. Therefore, the final structure of 2-quinoxalinol imines is3ae.

The higher reactivity of the 6-amino group versus the 7-amino group maybe explained based on either a kinetic or a thermodynamic argument. Inthe kinetic explanation, the 2-quinoxalinol ring is an aromatic system,and the 2-hydroxyl group is an electron-donor group which increaseselectron density of the carbon contacting 6-amino group and so making6-amino group more reactive than the 7-amino group (an α-nucleophileeffect). This effect is evident in the ¹H-NMR of intermediate 1 (FIG.2). There is a substantial difference between the chemical shift ofhydrogen on 6 and 7 amino groups (Δδ=0.81 ppm, as identified in thelabeling study). The two amino groups are in the same benzene ring, theup-field hydrogen of the 6-amino group must have more electron densityand, therefore, the 6-amino group is more reactive than the 7-aminogroup downfield.

This can be confirmed by computational results. The density functionaltheory method B3LYP/6-31G(d) was used to characterize intermediate (1)and 2-quinoxalinol imines (3a) and ground states in vacuum usingGaussian 03. Calculations using B3LYP/6-31G(d) were used for geometryoptimizations and the calculation of vibrational frequencies, whichconfirmed all stationary points as minima and provided thermodynamiccorrections. The effect of methanol was approximated by subsequentsingle-point calculations using the conductor-like polarizable continuummodel (CPCM). The default Gaussian 03 dielectric constant of 32.63 wasused for methanol. Partial charges for the intermediate (1) and2-quinoxalinol imines (3a) were obtained using CHELPG method. Thecalculation results show that the 6-nitrogen in each case has morenegative charge than the 7-nitrogen, and the 6-amino group of2-qunioxalinol should be more reactive that 7-amino group. (See Table3.)

TABLE 3 Calculation results of intermediate 1.

Charge of 6-nitrogen Charge of 7-nitrogen Intermediate R₁ (δ₆) (δ₇)≧δ₆₋₇ 1a

−0.857 −0.831 0.026 1b

−0.856 −0.831 0.025 1c

−0.861 −0.839 0.022 1d

−0.858 −0.817 0.039 1e H −0.852 −0.823 0.029

Finally, based on thermodynamics the minimized energy of three pair of2-quinoxalinol imines isomers (3ad and 3bd, 3af and 3bf and 3ai and 3bi)was calculated with the same method (vida supra) using a model of gasand methanol. The minimized energy of 3ad, 3af and 3ai are 0.869, 0.931and 0.954 lower in the gas model; and 0.800, 0.889 and 1.061 kcal/mollower in the MeOH model than their respective isomers (3bd, 3bf and3bi). Therefore, from the thermodynamic view, 3ad, 3af and 3ai are morestable than their isomers.

The synthetic method for the preparation of 2-quinoxalinol imines (3a)began with the addition of 1.0 equiv. of the intermediate (1) dissolvedin 4 mL methanol to a solution of 1.2 equiv substituted salicylaldehyde(2) in 6 mL methanol. The two were combined with stirring, and afterheating at refluxing temperature for 1 hour, the reaction mixturebecomes deep yellow or red. Stirring at refluxing temperature wascontinued for 14 hours, and monitored by TLC. Once it was observed thatthe reaction mixture no longer contains starting material (1), thereaction was stopped by allowing the mixture to cool to roomtemperature. Pure 2-quinoxalinol imines (3a) were obtained by flashcolumn chromatography using hexane:ethyl acetate, 3:1 as eluent.According to this method, eight different 2-quinoxalinol imines(3aa-3ah) were prepared (Table 4).

TABLE 4 Formation of 2-Quinoxalinol Imines (3ax). 3a

Product R₁ R₂ Yield (%) 3aa

3-tert-butyl 93.8* 3ab

3-tert-butyl 70.2* 3ac

3-tert-butyl 71.5* 3ad

3-tert-butyl 65.5* 3ae

3,5-Di-tert-butyl 76.7* 3af

3,5-Di-tert-butyl 66.0* 3ag

3,5-Di-tert-butyl 89.2* 3ah

3,5-Di-tert-butyl 80.0* 3ai

3-OH 68.5* 3aj H 3-tert-butyl —^(¶) 3ak H 3,5-Di-tert-butyl —^(¶)*One-step yield purified by column separation.

The yield of final products ranges from 65% to 94%. When R₁ was ahydrogen atom, the diamino-2-quinoxalinol (1e) was not stable and wasfound to decompose on exposure to air. Because of this, it was directlyused for the following reaction with 1.2 equiv salicylaldehyde undernitrogen gas protection without purification after the reductionreaction. The undehydrogenating diamino-2-quinoxalinol 1H reacts withthe salicylaldehyde derivative. The major byproducts were 3aj-1 (11.0%)and 3ak-1 (10.0%) and the expected products 3aj and 3ak was notobtained. For sample 3ai, a modified procedure was used. After heatingto reflux temperature for 4 hours, a red precipitate (3ai) forms. Thered solid was filtered off and washed with 95% ethanol followed byacetone resulting in the pure final 2-quinoxalinol imine (3ai). Unlikethe previous reactions, prolonging the reaction time did not increasethe yield of product (3ai). Other salicylaldehyde derivatives withdifferent functional groups in the 3 position were tried, but theexpected final 2-quinoxalinol imines (e.g., 3a) were not obtained. Incontrast, in some cases, low yields of the symmetric 2-quinoxalinolsalens were obtained. When the 3 position had bulky group such astert-butyl group, the 2-quinoxalinol imines (3a) were formed as themajor products. The compound 3ai is a special case, but when anotherintermediate (1) with different group R₁ reacted with 2,3-dihydroxysalicylaldehyde, the expected products were not formed. These resultsdemonstrate that the 2-quinoxalinol aromatic system and 3 position bulkygroup of salicylaldehyde are necessary to the regioselective effect. Allof the final products were identified and characterized by ¹H-NMR,¹³C-NMR, MS, HR-MS, and IR. In all cases, the R₁ groups areelectron-donor groups or are neutral (H). In the case of reactions withan electron-withdrawing group on R₁, such as with a trifluoromethylgroup, the resultant diamino-2-quinoxalinol was unstable, and its2-quinoxalinol imine was not obtained.

Based on these experiments, nine 2-quinoxalinol imines (3aa-3ai), andtwelve asymmetrically substituted 2-quinoxalinol salens (4aa-4l) wereobtained (Table 5).

TABLE 5 Formation of Asymmetrically Substituted 2-Quinoxalinol SalenLigands (4). 4

Pro- Yield duct R₁ R₂ R₃ (%)* 4a

3-tert-butyl 3,5-Di-tert-butyl 49.1 4b

3-tert-butyl H 60.5 4c

3,5-Di-tert-butyl 3-tert-butyl 41.0 4d

3-tert-butyl 3,5-Di-tert-butyl 54.2 4e

3-tert-butyl H 63.0 4f

3,5-Di-tert-butyl 3-tert-butyl 44.7 4g

3-tert-butyl 3,5-Di-tert-butyl 50.0 4h

3-tert-butyl H 68.5 4i

3,5-Di-tert-butyl 3-tert-butyl 38.5 4j

3-tert-butyl 3,5-Di-tert-butyl 50.5 4k

3-tert-butyl H 66.4 4l

3,5-Di-tert-butyl 3-tert-butyl 43.7 *Yield is a two step yield (i.e.,the yield from starting material 1 to final product 4).

The procedure for the synthesis of these asymmetrically substituted2-quinoxalinol salens is unique and can be done in one pot. According tothe general procedure of synthesis of 2-quinoxalinol imines 3a, when theimines are formed, without additional purification, a second substitutedsalicylaldehyde 2′ was directly added into the methanol reactionsolution. The reaction mixture was allowed to heat to reflux temperaturefor another 14 hours, and in the end, a precipitate forms. The endproduct can be filtered and washed with 95% ethanol and acetone 5 timeseach. The precipitates were directly identified by NMR and MS. Thepurities of them are very high. All of synthesized salens (4a-4l) are oflow solubility in water, hexane, methanol, or ethanol. When R₃ is H,these ligands are very soluble in DMSO or DMF, but not in DCM or CHCl₃,whereas other salens are, in contrast, soluble in DCM or CHCl₃, but oflow solubility in DMSO.

Combinations of different R₁, R₂ and R₃ groups were tested. Altering theR₁ group does not appear to affect the reactivity of 6,7-amino group.When intermediate 3a was reacted with the first salicylaldehyde 2containing the R₂ group being 3-tert-butyl, R₃ of the secondsalicylaldehyde 2′ added could be H or 3,5-di-tert-butyl and the yieldof these asymmetrically substituted 2-qunioxalinol salens (4a, 4b, 4d,4e, 4g, 4h, 4j and 4k) were 50.0%-70.0%, whereas when R₃ was a hydroxylgroup, there is no expected product; however, when R₂ is3,5-di-tert-butyl, there is only one combination which has a good yieldof the asymmetrically substituted 2-qunioxalinol salens, that is, R₃ is3-tert-butyl, the yield is a bit lower (˜45%).

Conclusion

The exact structure of 2-quinoxalinol imines was identified usingisotope ¹⁵N labeled compounds. Based on this, a series of new compounds,the 2-quinoxalinol imines were prepared and used to generate a series ofasymmetrically substituted 2-quinoxalinol salens. Using the iminefunctional group in these compounds, further asymmetrically salen ligandmay be generated using 2-quinoxalinol derivative prepared from naturalor artificial amino acids and labeled peptides, as well as secondaryamine products for screening for bioactivity. These asymmetrical2-quinoxalinol salen ligands further may be used to prepare metalcomplexes in order to identify their chiral character and developcomplexes as potential new chiral catalysts.

Experimental Section

All amino acid methyl esters, DFDNB (1,5-difluoro-2,4-dinitrobenzene),HCl (37%), Ammonium hydroxide (5.0 N), palladium on carbon (wet, 5%)were purchased and used as received. 15N labeled ammonium hydroxide waspurchased from Cambridge Isotope laboratories, Inc. All melting pointswere recorded, and the values were uncorrected. 1H and 13C NMR spectrawere recorded on a 250 MHz NMR spectrometer (operated at 250 and 62.5MHz, respectively) or 400 MHz spectrometer (operated at 400 and 100 MHz,respectively). Which instrument was used and when is indicated in thedata provided. Chemical shifts are reported as δ values (ppm). NMR datawere collected by using DMSO-d6. D2O/water exchange experiments were runin some experiments. The solvents used are indicted in the experimentaldetails. Reaction progress was monitored by thin-layer chromatography(TLC) using 0.25 mm silica gel precoated plates with visualization byirradiation with a UV lamp. HRMS data was collected using Electrosprayionization mass spectrometry or direct probe ionization. IRspectroscopic data was collected using KBr solid samples. Samples formelting point, IR and NMR were purified by flash column chromatography.Calculations were run using Gaussian 03.

General Procedure

3aa-3ai The synthesis of 2-quinoxalinol imine (3a) began with theaddition of 1.0 equiv of the intermediate 2-quinoxalinol (1) dissolvedin 4 mL methanol to a solution of 1.2 equiv. substituted salicylaldehydederivatives (2) in 6 mL methanol. The two were combined with stirringfor 14 hours, monitored by TLC. Once starting material (1) can no longerbe seen by TLC, the reaction was considered complete. Pure2-quinoxalinol imines (3a) were obtained by purification using flashcolumn chromatography with a solution of hexane:ethyl acetate, 3:1 aseluent. For sample (3ai), a modified procedure was used. The productbegan to form as a red solid (3ai) after heating at refluxingtemperature for 4 hours. The red solid was filtered off and washed with95% ethanol followed by acetone to obtain pure final 2-quinoxalinolimines (3ai).

4a-4i This procedure is the same as that for preparing the2-quinoxalinol imine; however, when the starting material (1) can nolonger be observed using TLC, a second salicylaldehyde derivative 2′ canbe added directly to the reaction mixture. The mixture was then allowedto heat at refluxing temperature for an additional 14 hours resulting ina large quantity of precipitates. These precipitates were isolated byfiltering, and then washed with 95% ethanol and acetone 5 times each.The pure products were identified and characterized by NMR, IR, MS andHRMS.

Experimental Data

3aa ¹H-NMR (400 MHz DMSO-d⁶): δ 1.44 (s, 9H), 4.04 (s, 2H), 5.84 (bs,2H), 6.59 (s, 1H), 6.80 (s, 1H), 6.59-7.74 (m, 9H), 8.98 (s, 1H), 12.15(bs, 1H), 13.58 (bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 167.4, 164.0,159.8, 155.5, 154.2 145.6, 138.8, 136.8, 133.4, 132.3, 132.2, 132.0,131.8, 130.4, 129.5, 129.2, 128.7, 126.6, 125.0, 120.0, 119.0, 117.1,97.7, 40.0, 35.0, 30.0. Formula: C₂₆H₂₆N₄O₂. MS (M+H): 426.0. HRMS:found (426.2051), calc (426.2056). IR: 3470.0 cm⁻¹ (bs), 3375.4 cm⁻¹(bs), 3182.6 cm⁻¹, 2956.9 cm⁻¹, 2927.9 cm⁻¹, 2870.1 cm⁻¹, 1728.2 cm⁻¹,1656.9 cm⁻¹, 1624.1 cm⁻¹, 1271.1 cm⁻¹. Melting point: 196.0-199.0° C.

3ab ¹H-NMR (400 MHz DMSO-d⁶): δ 1.20 (d, J=6.8, 6H), 1.44 (s, 9H), 3.61(sept, 1H), 5.77 (bs, 2H), 6.60 (s, 1H), 6.94 (t, 1H), 7.38 (d, 1H),7.53 (d, 1H), 7.55 (s, 1H), 9.03 (s, 1H), 12.07 (bs, 1H), 13.64 (bs,1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 170.8, 163.8, 159.8, 159.6, 155.1,145.3, 136.8, 133.1, 132.1, 131.8, 130.4, 124.8, 120.1, 119.0, 117.7,97.8, 35.0, 29.9, 20.8, 14.6. Formula: C₂₂H₂₆N₄O₂. MS (M+H): 378.0.HRMS: found (378.2052), calc (378.2056). IR: 3442.9 cm⁻¹ (bs), 3402.4cm⁻¹ (bs), 2958.8 cm⁻¹, 2872.0 cm⁻¹, 1710.9 cm⁻¹, 1651.1 cm⁻¹, 1626.0cm⁻¹, 1502.6 cm⁻¹, 1234.4 cm⁻¹. Melting point: 250.0-253.0° C. (Colorchanged).

3ac ¹H-NMR (250 MHz DMSO-d⁶): δ 0.93 (d, J=6.6, 6H), 1.43 (s, 9H), 2.19(m, 1H), 2.58 (d, 2H), 5.77 (bs, 2H), 6.59 (s, 1H), 6.93 (t, 1H), 7.37(d, 1H), 7.52 (d, 1H), 7.55 (s, 1H), 8.99 (s, 1H), 12.06 (bs, 1H), 13.62(bs, 1H). ¹³C-NMR (62.5 MHz, DMSO-d⁶): δ 163.8, 159.8, 155.8, 155.2,145.3, 136.8, 133.2, 132.1, 131.7, 130.4, 125.0, 120.3, 119.0, 117.6,97.8, 41.7, 34.9, 29.7, 26.8, 23.1. Formula: C₂₃H₂₈N₄O₂. MS (M+H):392.0. HRMS: found (392.2206), calc (392.2212). IR: 3392.8 cm⁻¹(bs),2954.9 cm⁻¹, 2924.1 cm⁻¹, 2866.2 cm⁻¹, 1710.0 cm⁻¹, 1626.0 cm⁻¹, 1600.9cm⁻¹, 1371.4 cm⁻¹, 1232.5 cm⁻¹. Melting point: >300.0° C.

3ad ¹H-NMR (250 MHz DMSO-d⁶): δ 1.43 (s, 9H), 2.09 (s, 3H), 2.86 (t,2H), 2.97 (t, 2H), 5.82 (bs, 2H), 6.59 (s, 1H), 6.93 (t, 1H), 7.37 (d,1H) 7.51 (d, 1H), 7.53 (s, 1H), 12.11 (bs, 1H), 13.59 (bs, 1H). ¹³C-NMR(62.5 MHz, DMSO-d⁶): δ 163.9, 159.8, 155.5, 153.9, 145.5, 136.8, 133.3,132.3, 131.8, 130.4, 125.0, 120.0, 119.0, 117.6, 97.8, 34.9, 32.8, 30.9,29.7, 15.2. Formula: C₂₂H₂₆N₄O₂S. MS (M+H): 410.0. HRMS: found(410.1767), calc (410.1776). IR: 3469.9 cm⁻¹(bs), 3334.9 cm⁻¹(bs),2920.2 cm⁻¹, 2954.9 cm⁻¹, 2918.3 cm⁻¹, 2875.9 cm⁻¹, 1710.8 cm⁻¹, 1662.6cm⁻¹, 1626.0 cm⁻¹, 1429.3 cm⁻¹, 1234.4 cm⁻¹. Melting point: 225.0-227.0°C.

3ae ¹H-NMR (400 MHz DMSO-d⁶): δ 1.31 (s, 9H), 1.44 (s, 9H), 4.05 (s,2H), 5.81 (bs, 2H, D₂O exchangeable), 6.58 (s, 1H), 7.20-7.55 (m, 8H),8.99 (s, 1H), 12.15 (bs, 1H, D₂O exchangeable), 13.32 (bs, 1H, D₂Oexchangeable). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 168.2, 162.4, 160.5, 159.5,145.7, 142.7, 141.4, 137.7, 137.5, 134.1, 133.0, 132.8, 131.8, 131.0,130.6, 123.4, 121.8, 102.9, 40.0, 39.8, 38.9, 36.2, 34.2. Formula:C₃₀H₃₄N₄O₂. MS: 482.0. HRMS: found (482.2681), calc (482.2682). IR:3491.2 cm⁻¹(bs), 3375.4 cm⁻¹, 2955.08 cm⁻¹, 2870.18 cm⁻¹, 2821.98 cm⁻¹,1718.68 cm⁻¹, 1653.0 cm⁻¹, 1626.0 cm⁻¹, 1502.6 cm⁻¹, 1238.0 cm⁻¹.Melting point: 248.0-250.0° C. 3ae ¹⁵N: ¹H-NMR (400 MHz DMSO-d⁶): δ 1.31(s, 9H), 1.44 (s, 9H), 4.04 (s, 2H), 5.81 (bs, 2H, D₂O exchangeable),6.58 (s, 1H), 7.21-7.55 (m, 8H), 8.98 (d, 1H), 12.14 (bs, 1H, D₂Oexchangeable), 13.32 (bs, 1H, D₂O exchangeable).

3af ¹H-NMR (400 MHz DMSO-d⁶): δ 1.18 (d, 6H), 1.26 (s, 9H), 1.28 (s,9H), 4.00 (sept, 1H), 5.67 (bs, 2H), 6.59 (s, 1H), 7.40 (s, 1H), 7.54(s, 1H), 7.58 (s, 1H), 9.04 (s, 1H), 12.06 (bs, 1H), 13.36 (bs, 1H).¹³C-NMR (100 MHz, DMSO-d⁶): δ 164.3, 159.6, 157.5, 155.1, 145.2, 140.7,136.0, 133.0, 132.3, 128.2, 127.4, 124.8, 119.4, 117.6, 97.7, 35.1,34.4, 31.8, 29.8, 20.8, 14.6. Formula: C₂₆H₃₄N₄O₂. MS (M+H): 434. HRMS:found (434.2675), calc (434.2682). IR: 3489.2 cm⁻¹(bs), 3387.0 cm⁻¹,2958.88 cm⁻¹, 2910.68 cm⁻¹, 2870.18 cm⁻¹, 2819.98 cm⁻¹, 1739.88 cm⁻¹,1651.1 cm⁻¹, 1620.2 cm⁻¹, 1502.6 cm⁻¹, 1240.1 cm⁻¹. Melting point:275.0-276.0° C. (Color changed).

3ag ¹H-NMR (400 MHz DMSO-d⁶): δ 0.94 (d, 6H), 1.32 (s, 9H), 1.44 (s,9H), 2.20 (m, 1H), 2.59 (d, 2H), 5.76 (bs, 2H), 6.59 (s, 1H), 7.40 (s,1H), 7.54 (s, 1H), 7.57 (s, 1H), 9.01 (s, 1H), 12.06 (bs, 1H), 13.36(bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 164.4, 157.5, 155.8, 155.0,145.3, 140.7, 136.0, 133.0, 132.4, 128.2, 127.5, 125.0, 119.4, 117.6,97.7, 41.7, 35.1, 34.4, 31.8, 29.8, 26.7, 23.1. Formula: C₂₇H₃₆N₄O₂. MS(M+H): 448.0. HRMS: found (448.2839), calc (448.2838). IR: 3489.2cm⁻¹(bs), 3400.5 cm⁻¹(bs), 2955.0 cm⁻¹, 2866.2 cm⁻¹, 2818.0 cm⁻¹, 1653.0cm⁻¹, 1626.0 cm⁻¹, 1500.6 cm⁻¹, 1234.4 cm⁻¹. Melting point: >300.0° C.

3ah ¹H-NMR (250 MHz DMSO-d⁶): δ 1.31 (s, 9H), 1.44 (s, 9H), 2.11 (s,2H), 2.83 (t, 2H), 2.96 (t, 2H), 5.80 (bs, 2H), 6.59 (s, 1H), 7.40 (s,1H), 7.56 (s, 1H), 7.70 (s, 1H), 8.99 (s, 1H), 12.12 (bs, 1H), 13.33(bs, 1H). ¹³C-NMR (62.5 MHz, DMSO-d⁶): δ 164.5, 157.5, 155.5, 153.8,145.4, 140.7, 136.1, 133.2, 132.5, 128.2, 127.5, 125.0, 119.4, 117.6,97.6, 35.1, 34.4, 32.8, 31.8, 30.8, 29.8, 15.2. Formula: C₂₆H₃₄N₄O₂S MS(M+H): 467. HRMS: found (467.2475), calc (467.2480). IR: 3473.8cm⁻¹(bs), 3333.0 cm⁻¹(bs), 2956.8 cm⁻¹, 2912.5 cm⁻¹, 2870.1 cm⁻¹,1711.08 cm⁻¹, 1662.6 cm⁻¹, 1626.0 cm⁻¹, 1500.6 cm⁻¹, 1234.5 cm⁻¹.Melting point: 239.5-240.5° C.

3ai ¹H-NMR (400 MHz DMSO-d⁶): δ 4.04 (s, 2H), 5.87 (bs, 2H, D₂Oexchangeable), 6.57 (s, 1H), 6.78-7.34 (m, 8H), 7.49 (s, 1H), 8.94 (s,1H), 9.26 (bs, 1H, D₂O exchangeable), 12.13 (bs, 1H, D₂O exchangeable),12.47 (bs, 1H, D₂O exchangeable). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 162.6,155.5, 154.0, 149.0, 146.0, 145.8, 138.8, 133.4, 132.8, 129.5, 128.7,126.6, 124.9, 122.9, 120.8, 119.3, 119.2, 117.4, 97.5, 39.0. Formula:C₂₂H₁₈N₄O₃. MS (M+H): 387.0. HRMS: found (387.1452), calc (387.1457).IR: 3489.2 cm⁻¹(bs), 3429.4 cm⁻¹(bs), 3394.7 cm⁻¹(bs), 2941.4 cm⁻¹,2877.8 cm⁻¹, 2818.0 cm⁻¹, 1656.8 cm⁻¹, 1626.0 cm⁻¹, 1500.6 cm⁻¹, 1465.9cm⁻¹, 1275.0 cm⁻¹, 1236.4 cm⁻¹. Melting point: 260.0-261.0° C.

3aj-1 ¹H-NMR (400 MHz CDCl₃ and DMSO-d⁶): 1.40 (s, 9H), 1.41 (s, 9H),3.87 (s, 2H), 4.04 (t, 1H), 6.37-7.50 (m, 8H), 8.78 (s, 1H), 8.84 (s,1H), 10.49 (bs, 11H), 14.09 (bs, 1H), 14.16 (bs, 1H). ¹³C-NMR (100 MHz,CDCl₃ and DMSO-d⁶): δ 166.0, 163.8, 161.2, 160.3, 160.0, 137.9, 137.0,136.9, 135.7, 132.6, 131.6, 131.2, 130.0, 126.7, 119.7, 118.8, 105.5,103.7, 60.2, 34.9, 29.7. Formula: C₃₀H₃₄N₄O₃ MS (M): 498.3. HRMS: found(498.2628), calc (498.2631). IR: 3386.9 cm⁻¹(bs), 2955.8 cm⁻¹, 2877.8cm⁻¹, 2818.0 cm⁻¹, 1680.2 cm⁻¹, 1609.6 cm⁻¹, 1519.4 cm⁻¹, 1430.6 cm⁻¹,1303.4 cm⁻¹, 1143.5 cm⁻¹. Melting point: 255.0-256.0° C. (Colorchanged).

3ak-1 ¹H-NMR (400 MHz CDCl₃ and DMSO-d⁶): δ 1.35 (s, 18H), 1.47 (s,18H), 4.10 (s, 2H), 4.11 (t, 3H), 6.60 (s, 1H), 6.79 (s, 1H), 7.20-7.47(m, 4H), 8.63 (s, 1H), 8.67 (s, 1H), 9.38 (bs, 1H), 13.55 (bs, 1H),13.64 (bs, 1H). ¹³C-NMR (100 MHz, CDCl₃ and DMSO-d⁶): δ 169.7, 163.2,146.4, 145.3, 141.7, 133.1, 132.0, 123.1, 39.8, 38.9, 36.3, 34.2.Formula: C₃₈H₅₀N₄O₃ MS (M): 610.4. HRMS: found (610.3883), calc(610.3891). IR: 3489.2 cm⁻¹(bs), 3379.4 cm⁻¹(bs), 3232.1 cm⁻¹(bs),2957.0 cm⁻¹, 2871.0 cm⁻¹, 2869.0 cm⁻¹, 1709.1 cm⁻¹, 1686.0 cm⁻¹, 1614.6cm⁻¹, 1515.0 cm⁻¹, 1297.5 cm⁻¹, 1250.5 cm⁻¹. Melting point: 250.0-251.0°C. (Color Changed).

4a ¹H-NMR (400 MHz DMSO-d⁶): δ 1.31 (s, 9H), 1.36 (s, 9H), 1.42 (s, 9H),4.18 (s, 2H) 6.90-7.56 (m, 1H), 7.97 (s, 1H), 8.94 (s, 1H), 9.13 (s,1H), 13.49 (bs, 1H, D₂O exchangeable), 14.01 (bs, 1H, D₂O exchangeable)¹³C-NMR (100 MHz, DMSO-d⁶): (167.1, 164.9, 160.4, 158.4, 145.0, 140.7,138.2, 137.8, 137.2, 136.7, 131.7, 130.6, 129.6, 128.6, 128.1, 126.7,119.6, 118.6, 118.3, 35.1, 34.9, 34.3, 31.7, 29.7, 29.6, 25.7. Formula:C₄₁H₄₆N₄O₃ MS (M⁺): 642.0. HRMS: found (642.3559), calc (642.3570). IR:3437.2 cm⁻¹(bs), 3423.7 cm⁻¹(bs), 2955.4 cm⁻¹, 2910.6 cm⁻¹, 2870.1 cm⁻¹,1658.8 cm⁻¹, 1610.6 cm⁻¹, 1577.8 cm⁻¹, 1431.2.9 cm⁻¹, 1392.6.0 cm⁻¹,1195.9 cm⁻¹, 1168.9 cm⁻¹. Melting point: 251.0-253.0° C.

4b ¹H-NMR (400 MHz DMSO-d⁶): , 1.38 (s, 9H), 4.17 (s, 2H), 6.88-7.88 (m,13H), 7.96 (s, 1H), 8.90 (s, 1H), 9.11 (s, 1H), 12.12 (bs, 2H), 14.46(bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 164.7, 164.2, 160.8, 160.5,155.0, 146.2, 137.9, 137.3, 137.1, 134.4, 132.2, 132.0, 131.7, 131.1,130.6, 129.7, 128.9, 126.9, 120.5, 119.7, 119.6, 118.7, 118.0, 117.0,105.7. Formula: C₃₃H₃₀N₄O₃ MS (M⁺): 387.0. HRMS: found (530.2320), calc(530.2318). IR: 3425.6 cm⁻¹(bs), 3147.8 cm⁻¹(bs), 3394.7 cm⁻¹(bs),2920.2 cm⁻¹, 2864.3 cm⁻¹, 2785.2 cm⁻¹, 1660.7 cm⁻¹, 1608.6 cm⁻¹, 1483.3cm⁻¹, 1384.9 cm⁻¹, 1201.7 cm⁻¹, 1147.7 cm⁻¹. Melting point: 239.0-241.0°C.

4c ¹H-NMR (400 MHz CDCl₃ and DMSO-d⁶): δ 1.30 (s, 9H), 1.37 (s, 9H),1.40 (s, 9H) 4.17 (s, 2H), 6.89-7.89 (m, 1H), 7.91 (s, 1H), 8.86 (s,1H), 9.07 (s, 1H), 12.53 (bs, 1H), 13.65 (bs, 1H), 13.68 (bs, 1H).¹³C-NMR (100 MHz, CDCl₃ and DMSO-d⁶): δ 166.8, 166.7, 165.7, 160.7,160.6, 160.4, 158.1, 154.9, 151.7, 144.6, 140.5, 138.4, 137.7, 137.2,137.0, 136.3, 132.1, 131.8, 131.5, 131.2, 129.6, 128.7, 128.1, 127.9,126.7, 119.6, 119.3, 118.9, 118.3, 105.9, 35.0, 34.9, 34.3, 31.9, 31.7,29.6. Formula: C₄₁H₄₆N₄O₃. MS (M⁺): 642.0. HRMS: found (642.3583), calc(642.3570). IR: 3373.5 cm⁻¹(bs), 2956.9 cm⁻¹, 2924.1 cm⁻¹, 2866.2 cm⁻¹,1654.9 cm⁻¹, 1602.9 cm⁻¹, 1275.0 cm⁻¹, 1488.8 cm⁻¹, 1203.9 cm⁻¹, 1174.7cm⁻¹. Melting point: 260.0-262.0° C.

4d ¹H-NMR (400 MHz CDCl₃ and DMSO-d⁶): δ 1.17 (s, 9H), 1.25 (s, 9H),1.29 (s, 9H), 2.04 (s, 3H), 2.87 (t, 2H), 3.08 (t, 2H), 6.70-7.54 (m,7H), 8.52 (s, 1H), 8.61 (s, 1H), 12.13 (bs, 1H), 13.15 (bs, 1H), 13.50(bs, 1H). ¹³C-NMR (100 MHz, CDCl₃ and DMSO-d⁶): δ 165.8, 165.5, 164.2,160.7, 159.9, 159.8, 158.5, 158.2, 155.3, 144.9, 144.6, 140.5, 140.4,138.9, 138.6, 137.7, 137.0, 136.9, 131.5, 131.4, 131.2, 130.8, 128.7,128.1, 127.0, 126.8, 118.8, 118.2, 105.6, 35.0, 34.8, 34.1, 33.1, 30.6,29.3, 29.2, 15.4. Formula: C₃₇H₄₆N₄O₃S MS (M⁺): 626.0. HRMS: found(626.3279), calc (626.3291). IR: 3421.7 cm⁻¹(bs), 2953.0 cm⁻¹(bs),2914.4 cm⁻¹(bs), 2862.4 cm⁻¹, 1656.9 cm⁻¹, 1610.6 cm⁻¹, 1577.8 cm⁻¹,1431.2 cm⁻¹, 1313.5 cm⁻¹, 1267.2 cm⁻¹. Melting point: 244.0-245.0° C.(Color changed).

4c ¹H-NMR (400 MHz DMSO-d⁶): δ 1.38 (s, 9H), 2.15 (s, 3H), 2.94 (t, 2H),3.13 (t, 2H), 6.89-7.99 (m, 9H), 8.92 (s, 1H), 9.13 (s, 1H), 11.99 (bs,1H), 12.49 (bs, 1H), 14.47 (bs, 1H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ164.6, 164.1, 160.8, 160.5, 154.8, 146.0, 137.3, 137.1, 134.4, 132.1,132.0, 131.7, 131.0, 130.6, 120.5, 119.7, 119.6, 118.7, 118.0, 117.0,105.7, 34.9, 33.2, 30.5, 29.6, 15.2. Formula: C₂₉H₃₀N₄O₃S MS (M⁺):514.0. HRMS: found (514.2039), calc (514.2039). IR: 3419.8 cm⁻¹(bs),2914.4 cm⁻¹, 2864.3 cm⁻¹, 2787.1 cm⁻¹, 1658.8 cm⁻¹, 1608.6 cm⁻¹, 1483.3cm⁻¹, 1392.6 cm⁻¹, 1207.4 cm⁻¹, 1143.8 cm⁻¹. Melting point: 229.0-230.0°C. (Color changed).

4f ¹H-NMR (400 MHz CDCl₃ and DMSO-d⁶): δ 0.92 (s, 9H), 1.01 (s, 9H),1.04 (s, 9H), 1.80 (s, 3H), 2.62 (t, 2H), 2.82 (t, 2H), 6.46-7.31 (m,7H), 8.28 (s, 1H), 8.40 (s, 1H). ¹³C-NMR (100 MHz, CDCl₃ and DMSO-d⁶): δ170.4, 170.3, 169.1, 168.6, 165.5, 165.3, 164.9, 163.0, 149.4, 149.3,145.3, 143.7, 143.4, 142.5, 141.7, 138.9, 136.9, 136.4, 136.2, 135.9,135.5, 135.3, 133.0, 131.8, 123.9, 123.7, 123.1, 122.7, 39.6, 39.0,38.0, 37.9, 36.2, 35.4, 34.1, 34.0, 20.2. Formula: C₃₇H₄₆N₄O₃S. MS (M⁺):626.0. HRMS: found (626.3277), calc (626.3291). IR: 3466.1 cm⁻¹(bs),3329.1 cm⁻¹(bs), 2955.0 cm⁻¹, 2899.0 cm⁻¹, 2873.9 cm⁻¹, 1662.6 cm⁻¹,1618.3 cm⁻¹, 1492.9.6 cm⁻¹, 1427.3 cm⁻¹, 1236.4 cm⁻¹, 1205.5 cm⁻¹,1172.7 cm⁻¹. Melting point: 240.0-241.0olor changed).

4g ¹H-NMR (400 MHz CDCl₃ and DMSO-d⁶): δ 0.92 (d, 6H), 1.22 (s, 9H),1.30 (s, 9H), 1.32 (s, 9H), 2.24 (m, 1H), 2.69 (d, 2H), 6.74-7.58 (m,7H), 8.58 (s, 1H), 8.66 (s, 1H). 13.23 (bs, 1H), 13.41 (bs, 1H), 13.56(bs, 1H). ¹³C-NMR (100 MHz, CDCl₃ and DMSO-d₆): δ 165.0, 164.0, 163.0,160.5, 158.6, 155.7, 144.7, 144.5, 140.5, 138.6, 137.7, 137.6, 137.1,131.4, 131.1, 130.9, 130.7, 130.5, 128.7, 127.1, 119.1, 118.9, 118.3,118.1, 117.8, 105.6, 42.1, 35.0, 34.8, 34.1, 31.4, 29.4, 29.3, 26.7,22.7. Formula: C₃₈H₄₈N₄O₃ MS (M⁺): 608.0. HRMS: found (608.3730), calc(608.3726). IR: 3421.7 cm⁻¹(bs), 2955.0 cm⁻¹(bs), 2910.6 cm⁻¹(bs),2872.0 cm⁻¹, 1662.6 cm⁻¹,1606.7 cm⁻¹, 1492.9 cm⁻¹, 1425.4 cm⁻¹, 1317.4cm⁻¹, 1276.9 cm⁻¹, 11134.1 cm⁻¹, 1089.8 cm⁻¹. Melting point:260.0-261.0° C. (Color changed).

4h ¹H-NMR (250 MHz DMSO-d⁶): δ 0.98 (d, 6H), 1.37 (s, 9H), 2.27 (m, 1H),2.70 (d, 2H), 6.86-7.98 (m, 9H), 8.90 (s, 1H), 9.12 (s, 1H). 12.36 (bs,1H), 14.01 (bs, 1H), 14.48 (bs, 1H). ¹³C-NMR (62.5 MHz, DMSO-d⁶): δ164.5, 164.1, 161.9, 161.6, 160.8, 160.5, 155.2, 145.8, 144.5, 137.9,137.2, 137.1, 137.0, 134.3, 132.2, 132.0, 131.6, 131.4, 131.1, 130.7,130.6, 120.5, 119.7, 119.6, 119.4, 119.1, 118.9, 118.6, 118.1, 117.9,117.0, 105.8, 42.1, 34.9, 29.7, 26.6, 23.1. Formula: C₂₀H₃₂N₄O₃ MS (M⁺):496.0. HRMS: found (496.2472), calc (496.2474). IR: 3435.2 cm⁻¹(bs),3423.7 cm⁻¹(bs), 2953.0 cm⁻¹, 2916.4 cm⁻¹, 2868.2 cm⁻¹, 1656.9 cm⁻¹,1610.6 cm⁻¹, 1473.6 cm⁻¹, 1431.2 cm⁻¹, 1392.6 cm⁻¹, 1276.8 cm⁻¹, 1193.9cm⁻¹, 1143.8 cm⁻¹. Melting point: 271.0-273.0° C. (Color changed).

4i ¹H-NMR (400 MHz CDCl₃ and DMSO-d⁶): δ 0.91 (d, 6H), 1.22 (s, 9H),1.28 (s, 9H), 1.32 (s, 9H), 2.23 (m, 1H), 2.69 (d, 2H), 6.73-7.58 (m,7H), 8.58 (s, 1H), 8.66 (s, 1H). 13.22 (bs, 1H), 13.41 (bs, 1H), 13.56(bs, 1H). ¹³C-NMR (100 MHz, CDCl₃ and DMSO-d⁶): δ 165.9, 165.2, 163.7,161.8, 161.6, 160.7, 158.6, 155.7, 144.7, 144.4, 140.5, 138.6, 137.7,137.6, 137.1, 131.4, 131.1, 131.0, 130.9, 130.7, 130.5, 128.7, 127.1,119.1, 118.9, 118.3, 118.1, 117.7, 105.5, 42.1, 35.0, 34.8, 34.7, 31.4,29.3, 29.2, 26.8, 22.7. Formula: C₃₈H₄₈N₄O₃ MS (M⁺): 608.0. HRMS: found(608.3721), calc (608.3726). IR: 3500.0 cm⁻¹(bs), 2955.0 cm⁻¹(bs),2912.5 cm⁻¹(bs), 2872.0 cm⁻¹, 1662.6 cm⁻¹, 1604.8 cm⁻¹, 1492.9 cm⁻¹,1431.2 cm⁻¹, 1356.6 cm⁻¹, 1207.4 cm⁻¹, 1138.0 cm⁻¹. Melting point:264.0-266.0° C.

4j ¹H-NMR (400 MHz CDCl₃ and DMSO-d⁶): δ 1.21 (d, 6H), 1.30 (s, 9H),1.33 (s, 9H), 1.34 (s, 9H), 3.49 (m, 1H), 6.74-7.61 (m, 7H), 8.57 (s,1H), 8.68 (s, 1H). 12.05 (bs, 1H), 13.22 (bs, 1H), 13.58 (bs, 1H).¹³C-NMR (100 MHz, CDCl₃ and DMSO-d⁶): δ 165.4, 163.5, 160.7, 160.5,158.6, 158.1, 155.1, 144.7, 144.4, 140.5, 138.5, 137.8, 137.6, 137.1,131.5, 131.3, 131.0, 130.9, 130.7, 130.4, 128.7, 127.1, 119.1, 118.9,118.3, 118.2, 118.1, 117.9, 105.4, 35.0, 34.8, 34.1, 31.4, 30.3, 29.4,29.3, 20.2. Formula: C₃₇H₄₆N₄O₃. MS (M⁺): 594.0. HRMS: found (594.3566),calc (594.3570). IR: 3415.9 cm⁻¹(bs), 3138.2 cm⁻¹(bs), 2955.0 cm⁻¹,2872.0 cm⁻¹, 2792.9 cm⁻¹, 1664.6 cm⁻¹, 1606.7 cm⁻¹, 1489.1 cm⁻¹, 1479.4cm⁻¹, 1211.3 cm⁻¹, 1184.3 cm⁻¹. Melting point: 269.0-271.0° C.

4k ¹H-NMR (400 MHz CDCl₃ and DMSO-d⁶): δ 1.27 (d, 6H), 1.38 (s, 9H),3.51 (m, 1H), 6.89-7.99 (m, 9H), 8.91 (s, 1H), 9.16 (s, 1H). 12.06 (bs,1H), 12.43 (bs, 1H), 14.52 (bs, 1H). ¹³C-NMR (100 MHz, CDCl₃ andDMSO-d⁶): δ 164.6, 164.1, 161.0, 160.9, 160.6, 160.5, 154.6, 145.9,137.2, 137.1, 134.4, 133.1, 132.0, 131.7, 131.0, 130.6, 120.6, 120.1,119.7, 119.6, 119.5, 118.7, 118.1, 117.9, 117.2, 117.0, 105.6, 34.9,30.4, 29.6, 20.6. Formula: C₂₉H₃₀N₄O₃, MS (M⁺): 482.0. HRMS: found(482.2313), calc (482.2318). IR: 3448.7 cm⁻¹(bs), 3145.9 cm⁻¹(bs),2958.8 cm⁻¹, 2870.1 cm⁻¹, 2794.9 cm⁻¹, 1658.8 cm⁻¹, 1610.6 cm⁻¹, 1481.3cm⁻¹, 1384.9 cm⁻¹, 1207.4 cm⁻¹, 1147.7 cm⁻¹. Melting point: 265.0-267.0°C.

4l ¹H-NMR (400 MHz CDCl₃ and DMSO-d⁶): δ 1.19-1.30 (m, 33H), 3.47 (m,1H), 6.72-7.59 (m, 7H), 8.57 (s, 1H), 8.67 (s, 1H). 12.02 (bs, 1H),13.35 (bs, 1H), 13.43 (bs, 1H). ¹³C-NMR (100 MHz, CDCl₃ and DMSO-d⁶): δ166.0, 165.4, 164.2, 160.7, 158.3, 155.0, 144.3, 140.4, 138.8, 137.7,136.9, 131.5, 131.1, 131.0, 130.8, 128.1, 126.9, 118.9, 118.3, 118.2,117.9, 105.5, 34.9, 34.7, 34.1, 31.3, 30.3, 29.3, 29.2, 20.1. Formula:C₃₇H₄₆N₄O₃, MS (M⁺): 594.0. HRMS: found (594.3572), calc (594.3570). IR:3417.9 cm⁻¹(bs), 3142.0 cm⁻¹(bs), 2956.9 cm⁻¹, 2877.8 cm⁻¹, 2868.2 cm⁻¹,1656.9 cm⁻¹, 1606.7 cm⁻¹, 1469.8 cm⁻¹, 1433.1 cm⁻¹, 1209.4 cm⁻¹, 1172.7cm⁻¹. Melting point: 258.0-260.0° C.

Example 2 References

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Example 3

Reference is made to Wu et al., “Synthesis and Characterization of2-Quinoxalinol Schiff-Base Metal Complexes,” Inorganica Chimica Acta,Volume 362, Issue 6, 20 Apr. 2009, Pages 1847-1854, the content of whichis incorporated herein by reference in its entirety.

Abstract

The reaction of uranyl acetate with(2,2′-(1E,1′E)-(2-benzyl-3-hydroxyquinoxaline-6,7 diyl)bis(azan-1-yl-1-ylidene) bis(methan-1-yl-1-ylidene) diphenol) (H₂L1) atroom temperature in methanol and chloroform yields the UO₂L1 complex.Crystals were grown through solvent diffusion of the ligand-metalcomplex in dimethyl formamide with diethyl ether to prepare: UO₂L1.DMF(1). Complexes with2,2′-(1E,1′E)-(2-benzyl-3-hydroxyquinoxaline-6,7-diyl)bis(azan-1-yl-1-ylidene)bis(methan-1-yl-1-ylidene)dibenzene-1,4-diol,(H₂L2) and2,2′-(1E,1′E)-(2-hydroxy-3-isopropylquinoxaline-6,7-diyl)bis(azan-1-yl-1-ylidene)bis(methan-1-yl-1-ylidene)diphenol(H₂L3) were also prepared, and crystals of the uranyl complexes(UO₂L2.DMF (2) and (3)) grown from DMF/ether. A fourth complex UO₂L4.H₂O(4) was prepared through layering a solution of the tetra-tert butylsubstituted 2-quinoxalinol salen ligand H₂L4 in acetone with an aqueoussolution containing uranyl acetate. The complexes exhibit a symmetriccore featuring a slightly distorted bicapped pentagonal geometry aroundthe uranium center with two oxo-groups and two imine groups from theligand chelating the ligand and the fifth site in the coordination planeof the ligand occupied by a solvent molecule. These compounds werecharacterized using solution (NMR and UV-Vis) and solid-state (1R, X-raycrystallography) techniques. Complexes of H₂L4 with early transitionmetals; Mn²⁺, Co²⁺, Ni²⁺, and Cu²⁺ also were prepared and characterizedfor comparison of solution and spectroscopic characteristics.

Introduction

One proposal to limit greenhouse gases is to increase the use ofelectrical power production using nuclear fuels; however, this hascaused wide spread public concern about the possible health hazards thatmight result from environmental contamination with the actinides (U, Np,Pu), which are both radioactive and chemically toxic heavy metals.Prolonged exposure or ingestion of quantities of uranium, principallyfound as uranyl ion (UO₂ ²⁺) under environmental or aqueous conditions,can lead to damage of kidney and/or liver function, through a mechanismmuch like other heavy metals. A resurgence of interest in actinidecoordination chemistry is founded on improving understanding ofenvironmental transport and long term storage solid forms in order tobetter address these health and environmental concerns. Here, a newseries of ligands incorporating a quinoxaline into a salen backbone weresynthesized. These new ligands may be used to facilitate remediation ofcontaminated sites and for decontamination applications.

Various ligand systems have been proposed for the selective extractionof uranium including organic phosphorus oxides, crown ethers,calixarenes, and Schiff bases. Many of these have also been proposed foruse in actinide selective sensors; however, their use in applicationsmight be limited by sensitivity, signal response, and competition fromother metals. A good sensor for uranium must be: highly selective,provide a large signal response, and allow for isolation and recovery ofthe metal. New ligand systems will be required that can both addressthese limitations in a variety of solvent and pH conditions and thatpossess the capacity to allow for modifications to tailor selectivity orsolubility for incorporation into applications.

While using the inherent radioactivity of the actinides is one way todetect these radioactive heavy metals, the methods to remediate wastesfrom medical radioactive waste would be very different than cleaning upmaterials containing actinides from nuclear fuels. Typical handheldradiation detectors could not distinguish between the two. A Geigercounter only detects beta and gamma emissions, not alpha emissions, andwhile uranium emits both alpha and beta emissions, Tc⁹⁹ (used in medicaltracer studies), is a strong beta emitter. This might lead one to notrealize the quantities of radioactive material present. Also, someisotopes such as ²³⁹Pu are entirely alpha-emitters, and would not bedetected by a Geiger counter, since these are β and γ-emissiondetectors. Only the daughter products would be detected. Finally,emissions could be masked by the presence of other metals or insolutions. Uranium has a natural fluorescence, but this is reduced orquenched in some minerals containing other metals. A chemical orfluorescent sensor could be useful in rapid field identification ofactinides and in decontaminations and could increase sensitivity ofdetection by reducing detection limits.

Currently used methods for the determination of heavy metal ionconcentration in groundwater and soils are based on atomic absorptionspectroscopy (AA), but this technique has a low sensitivity for uranium.Kinetic phosphorimetry (KPA) or ultraviolet-visible spectroscopy(UV-Vis) with a coordinating dye such as Arsenazo III have improvedsensitivity, but both techniques are complicated by organic compoundsand require that samples be purified prior to measurements. Other ligandsystems found to be selective for uranyl (UO₂ ²⁺) demonstrate a falsesignal with first row transition metals, in particular Cu²⁺. Thus,detection and quantification of uranium from environmental samples canbe quite complicated, and it is dependent on purification of the sampleprior to measurement.

In the design of the 2-quinoxolinol salen ligands, the addition of aquinoxaline functionality to the salen imparts the fluorescence of thequinoxaline and alters the flexibility of the coordination site throughthe addition of the aromatic backbone. This aromatic system will alsocontribute to the intensity of absorption in the UV-Vis of the complex.Salen or salophen ligands have been used as transition metal complexesin a variety of applications. For example, Cu, Mn, or Ru complexes havebeen used as catalysts in the catalytic oxidation of secondary amines,in enantioselective catalysts, and as catalysts for ring-openingmetathesis. Uranyl metal salophens have been used in molecularrecognition studies as anion receptors or in other studies probingchemical reactivity of the metal complex.

Therefore, 2-quinoxalinol ligands were prepared and modified for use inrecognizing uranyl. A Schiff-base condensation of a benzaldehyde withthe diaminoquinoxaline results in ligands based on the skeleton2,2′-(1E,1′E)-(quinoxaline-6,7-diylbis (azan-1-yl -1-ylidene))bis(methan-1-yl-1-ylidene) diphenol. (Scheme 4.) Here, four uranlylmetal complexes with 2-quinoxalinol salen ligands are reported and arecharacterized by X-ray diffraction. (See Scheme 5.) All of the metalcomplexes are characterized by ¹H-NMR or mass spec, and compared withultraviolet-visible spectroscopy. Complexes with early transition metalsare also described with Mn²⁺, Co²⁺, Ni²⁺, and Cu²⁺ to compare thespectroscopy of the complexes. (See Scheme 6.) The results describedhere will contribute to the development of actinide selective sensors.

Experimental Section

General Procedure

Aminoacid methyl esters, difluorodinitrobenzene (DFDNB), HCl (37%) andfunctionalized salicylaldehydes were purchased from Acros Organics Co.Ammonium hydroxide (5.0 N), palladium on carbon (wet, 5%) was purchasedfrom Sigma-Aldrich Co. Copper (II) acetate, Ni (II) acetate, Mn (II)acetate, Co (II) acetate, uranyl (UO₂ ²⁺) acetate not currentlyavailable were purchased from Sigma-Aldrich Co. Starting materials wereused as received. All organic solvents were purchased from Thermo FisherScientific Co. and were used directly for synthesis.

Reaction progress was monitored by thin-layer chromatography (TLC) using0.25 mm Whatman Aluminum silica gel 60-F254 precoated plates withvisualization by irradiation with a Mineralight UVGL-25 lamp. Allmelting points were recorded on a MeI-temp II melting point apparatus,and the values were uncorrected. The ¹H and ¹³C NMR spectra wererecorded on Bruker AV 400 spectrometer with d6-DMSO and d4-MeOH assolvents with tetramethylsilane as the reference (operated at 400 and100 MHz, respectively). Chemical shifts are reported as δ values (ppm).Electrospray ionization mass spectrometry was performed on a MicromassQTOF mass spectrometer (Waters Corp, Milford Mass.). Direct probesamples were on a VG-70S mass spectrometer (Waters Corp, Milford Mass.).All UV data was collected using a Cary 50 UV-Vis spectrophotometer witha xenon lamp and an equipment range from 200 to 1250 nm. The IR datawere recorded as KBr pellets on SHIMADZU Inc. IR, Prestige-21 FourierTransform Infrared Spectrophotometer in the range 400-4000 cm⁻¹.

Ligand Synthesis

The ligands were prepared using a procedure modified from theliterature. To 1.0 equiv (0.1 mmol) of the diamino-2-quinoxalinolintermediate dissolved in 4 mL methanol, a solution of 10.0 equiv (1mmol) salicylaldehyde in 6 mL methanol was added. After heating atreflux temperature for 48 hours, a dark yellow product precipitates. Theprecipitate was filtered and washed with 95% ethanol and cold acetone 5times to obtain the final product. The yield of final products was closeto 80% with the purity 95%. All of the products were identified by ¹³C,¹H-NMR, IR, HRMS, and UV-Vis.

Synthesis of Metal Complexes

[UO₂(L1).DMF] (1): To a solution of H₂L1 (23.7 mg, 0.25 mmol) in 10 mLMeOH and CHCl₃ (1:1) uranyl acetate (UO₂(OAc)₂.2H₂O, 25.5 mg, 0.06 mmol)was added and stirred at room temperature for two hours. The solutionwas concentrated and washed with 95% EtOH to obtain 1. Yield: 80.7%(30.0 mg); δ_(H) (400 MHz DMSO-d⁶): δ 4.20 (s, 2H), 6.73-6.77 (t, 2H),7.00-7.04 (t, 2H), 7.24-7.88 (m, 10H), 8.12 (s, 1H), 9.60 (s, 1H), 9.76(s, 1H), 12.67 (bs, 1H). HRMS: obs: 784.2280, calc: 784.2285(M+H+CH₃CN). ν (KBr)/cm⁻¹: 3397, 3337, 2965, 1657, 1620, 1582, 1545,1491, 1445, 1204, 1144, 1040 cm⁻¹. UV-Vis (DMSO): 290 nm (∈=2.0×10⁴),370 nm (∈=1.5×10⁴). A portion of the dark red solid (10 mg) wasdissolved in 1 mL dimethylformamide (DMF) and put into a vial. Intothis, diethyl ether was allowed to diffuse into from an outer vial.After 2 weeks, the formation of red crystals as thin needles wasobserved.

[UO₂(L2).DMF] (2): To a solution of H₂L2 (25.3 mg, 0.05 mmol) in 6 mLDMF and MeOH (50:50), uranyl acetate (UO₂(OAc)₂.2H₂O, 25.5 mg, 0.06mmol) was added and the resulting mixture was stirred at roomtemperature for two hours. The solution was concentrated and washed with95% EtOH to obtain 2. Yield: 85.9% (33.3 mg); δ_(H) (400 MHz DMSO-d⁶): δ4.22 (s, 2H), 6.54-8.67 (m, 13H), 9.55 (s, 1H), 9.71 (s, 1H), 11.77 (bs,1H), 11.82 (bs, 1H), 12.69 (bs, 1H). HRMS: obs: 816.2178, calc: 816.2183(M+H+ CH₃CN). ν (KBr)/cm⁻¹: 3397, 3337, 2965, 1657, 1620, 1582, 1545,1491, 1445, 1204, 903 cm⁻¹. UV-Vis (DMF): 365 nm (∈=1.10×10⁴), A portionof the dark red solid (10 mg) was dissolved in 1 mL of dimethylformamide(DMF) in a vial. Into this, diethyl ether was allowed to diffuse intofrom an outer vial. After 2 weeks, the formation of red crystals as thinneedles was observed.

[UO₂(L3).DMF] (3): To a solution of H₂L3 (106.6 mg, 0.25 mmol) in 60 mLMeOH and 100 mL THF, uranyl acetate (UO₂(OAc)₂.2H₂O, 130 mg, 0.30 mmol)was added. The solution turned dark red upon addition of metal salt.After stirring at room temperature for 2 hours, the solution wasconcentrated and washed with 95% EtOH. Yield: 97.8% (170 mg). δ_(H) (400MHz DMSO-d⁶): δ 1.28 (d, 6H), 3.56 (m, 1H), 6.74-8.17 (m, 10H), 9.61 (s,1H), 9.81 (s, 1H), 12.58 (bs, 1H). HRMS: obs: 736.2280, calc: 736.2285(M+H+CH₃CN). ν (KBr)/cm⁻¹: 3406, 2967, 1655, 1601, 1539, 1464, 1441,1263, 1146, 899 cm⁻¹. UV-Vis (DMF): 287 nm (∈=1.7×10⁴), 304 nm(∈=1.6×10⁴), 360 nm (∈=1.3×10⁴), 385 nm (∈=1.3×10⁴), 419 nm (∈=1.4×10⁴).A portion of the dark red solid (10 mg) was dissolved in 1 mLdimethylformamide (DMF) and put into a vial. Into this, diethyl etherwas allowed to diffuse into from an outer vial. After 2 weeks, theformation of red crystals as thin needles was observed.

[UO₂(L4).1H₂O] (4): To a solution of H₂L4 (35.0 mg, 0.05 mmol) in 6 mLMeOH and 6 mL CHCl₃, uranyl acetate (UO₂(OAc)₂.2H₂O, 25.5 mg, 0.06 mmol)was added. The solution turned dark red upon addition of metal salt.After stirring at room temperature, for 2 hours, the solution wasconcentrated. Yield: 77.1% (37.3 mg). In a second preparative method, anaqueous solution of uranium acetate (10 mg in 1 mL) was layered with asaturated acetone solution of ligand H₂L4 (10 mg in 1 mL). The acetonesolution was seen to turn red at the interface. After one week, crystalsas red rods were seen to form at the interface of the two layers, andthe crystalline material was collected (Yield: 80%). This was identifiedas [UO₂(L4).H₂O] and characterized by XRD. δ_(H) (400 MHzCDCl₃+DMSO-d⁶): δ 1.19 (s, 18H), 1.64 (s, 18H), 4.11 (s, 2H), 7.09-7.63(m, 10H), 7.70 (s, 1H), 9.19 (s, 1H), 9.32 (s, 1H), 12.18 (bs, 1H).HRMS: obs: 967.4514, calc: 967.4524 (M+H). ν (KBr)/cm⁻¹: 3433, 2957,1655, 1620, 1383, 1283, 1229, 1153, 937, 760 cm⁻¹. UV-Vis DMSO: 295 nm(∈=2.5×10⁴), 375 nm (∈=1.6×10⁴), and 440 nm (∈=1.5×10⁴).

[Co(L4).MeOH] (5): To a solution of H₂L4 (70 mg, 0.10 mmol) in 10 mLMeOH and CHCl₃ (1:1) an 1.1 molar amount of cobalt II acetate(Co(OAc)₂.4H₂O, 27 mg, 0.11 mmol) was added. After heating to refluxtemperature for 12 hours, the solution was concentrated and washed with95% EtOH. A dark black/blue precipitate was obtained by filtering.Yield: 79.4% (60.0 mg); HRMS: obs: 755.3369, calc: 755.3372 (M⁺)). ν(KBr)/cm⁻¹:3066, 2957, 1665, 1614, 1572, 1524, 1501, 1462, 1410, 1256,1180, 1128 cm⁻¹. UV-Vis (dichloromethane): 322 nm (∈=6.15×10⁴), 437 nm(∈=7.08×10⁴).

[Cu(L4).MeOH] (6): To a solution of H₂L4 (70 mg, 0.10 mmol) in 10 mLMeOH and CHCl₃ (1:1), copper II acetate (Cu(OAc)₂.1H₂O, 22 mg, 0.11mmol) was added. After heating to reflux temperature for 12 hours, thesolution was concentrated and washed with 95% EtOH. A dark precipitatewas obtained by filtering. Yield: 82.8% (63 mg); HRMS: obs: 760.3413,calc: 760.3422 (Mt).). ν(KBr)/cm⁻¹:3067, 2955, 1661, 1586, 1528, 1491,1416, 1377, 1260, 1209, 1173, 1130 cm⁻¹. UV-Vis (dichloromethane): 286nm (∈=6.13×10⁴), 330 nm (∈=7.54×10⁴), 458 nm (F=9.14×10⁴). DMSO: 280 nm(∈=3.4×10⁴), 32 5 nm (∈=2.8×10⁴), and 454 nm (∈=1.5×10⁴).

[Ni(L4).MeOH] (7): To a solution of H₂L4 (70.0 mg, 0.10 mmol) in 10 mLMeOH and CHCl₃ (1:1), nickel II acetate (Ni(OAc)₂94H₂O, 27 mg, 0.11mmol) was added. After heating to reflux temperature for 12 hours, thesolution was concentrated and washed with 95% EtOH. A green/brownprecipitate was obtained by filtering. Yield: 92.7% (70 mg); HRMS: obs:755.3461, calc: 755.3471 (M⁺)). ν (KBr)/cm⁻¹:3067, 2955, 2870, 1665,1616, 1584, 1533, 1598, 1464, 1414, 1379, 1260, 1182, 1130 cm⁻¹. UV-Vis(dichloromethane): 268 nm (∈=4.66×10⁴), 314 nm (∈=4.81×10⁴), 388 nm(∈=5.78×10⁴), 452 nm (∈=9.24×10⁴).

[Mn(L4).MeOH] (8): To a solution of H₂L4 (70.0 mg, 0.10 mmol) in 10 mLMeOH and CHCl₃ (1:1), manganese II acetate (Mn(OAc)₂.4H₂O, 27 mg, 0.11mmol) was added. After heating to reflux temperature for 12 hours, thesolution was concentrated and washed with 95% EtOH. A dark brownprecipitate was obtained by filtering. Yield: 96.5% (72.5 mg); HRMS:obs: 751.3420, calc: 751.3429 (M⁺). ν (KBr)/cm⁻¹: 3385, 3248, 3208,2955, 2911, 1670, 1582, 1532, 1462, 1416, 1317, 1248, 1177, 1130 cm⁻¹.UV-Vis (dichloromethane): 372 nm (∈=4.06×10⁴), 510 nm, (∈=7.13×10⁴).

Crystal Growth and X-Ray Crystallography

Crystals of uranyl metal complexes UO₂L1.DMF, UO₂L2.DMF, and UO₂L3.DMFwere obtained in good yield from slow diffusion of diethyl ether into asolution of the metal complex in dimethyl formamide at room temperature.Crystals of the UO₂L4.H₂O were grown by layering an aqueous solution ofuranyl acetate with a solution of ligand H₂L4 in acetone. Crystal ofcomplexes with the first row transition metals were found to not be of asuitable quality for characterization by X-ray diffraction. X-raydiffraction data for UO₂L1.DMF, UO₂L2.DMF. UO₂L3.DMF. and UO₂L4.H₂O werecollected at −80° C. on a Bruker SMART APEX CCD X-ray diffractometerunit using Mo Kα radiation from crystals mounted in Paratone-N oil onglass fibers. SMART (ν 5.624) was used for preliminary determination ofcell constants and data collection control. Determination of integratedintensities and global cell refinement were performed with the BrukerSAINT Software package using a narrow-frame integration algorithm. Theprogram suite SHELXTL (ν 6.12) was used for space group determination,structure solution, and refinement. Refinement was performed against F²by weighted full-matrix least square, and empirical absorptioncorrection (SADABS Sheldrick, G. M., SADABS—An empirical absorptioncorrection program; Bruker Analytical X-ray Systems Madison, Wis.,1996.) were applied. H atoms were placed at calculated positions usingsuitable riding models with isotropic displacement parameters derivedfrom their carrier atoms. Crystal data, selected bond distances andangles, are provided in Tables 6 and 7. Crystallography data forstructural analysis of uranyl complexes of compounds UO₂L1.DMF,UO₂L2.DMF. UO₂L3.DMF. and UO₂L4.H₂O have been deposited with theCambridge Crystallographic Data Center as CCDC nos. 650168, 673941,673940 and 650169, respectively.

TABLE 6 Crystallographic data for uranyl 2-quinoxolinol complexes1•(UO₂)²⁺, 2•(UO₂)²⁺, 3•(UO₂)²⁺ and 4•(UO₂)²⁺ Compounds 1•(UO₂)²⁺2•(UO₂)²⁺ 3•(UO₂)²⁺ 4•(UO₂)²⁺ Empirical formula C₃₂H₂₇N₅O₆UC_(32.75)H_(28.75)N_(5.25)O_(8.25)U C₂₈H₂₆N₅O₆U C₁₀₈H₁₄₆N₈O₁₉U₂ Fw(g/mol) 815.62 865.89 767.58 2336.39 Wavelength (Å) 0.71073 0.710730.71073 0.71073 Crystal system Monoclinic Monoclinic MonoclinicMonoclinic Space group C2/c C2/c C2/c P2₁/n Z 8 4 8 4 a (Å) 33.449(2)16.403(2) 26.074(2) Å 21.084(2) b (Å) 7.404(4) 7.196(4) 7.291(5) Å23.115(2) c (Å) 28.564(1) 28.974(3) 28.868(2) Å 23.334(2) a (deg) 90 9090 90 β (deg) 124.200(1) 93.968(3) 99.572(1) 107.461(1) g (deg) 90 90 9090 V (Å³) 5851.0(5) 3412.0(6) 5411.7(6) 10848(1) Density calc'd (g/cm³)1.852 1.686 1.882 1.431 Abs coeff (mm⁻¹) 5.603 4.814 6.051 3.050 F(000)3152 1680 2952 4744 Cryst size (mm³) 0.03 × 0.1 × 0.02 0.02 × 0.1 × 0.020.02 × 0.1 × 0.02 0.4 × 0.02 × 0.25 Reflns collected 28742 10978 1728194464 Indep reflns 7246 7362 6501 26956 [R_((int)) = 0.0603] [R_((int))= 0.0608] [R_((int)) = 0.0496] [R_((int)) = 0.0513] Refinements methodFull-matrix Least Full-matrix Least Full-matrix Least Full-matrix LeastSquares on F² Squares on F² Squares on F² Squares on F² GOF of F² 1.0251.030 0.950 0.950 Final R indices R₁ = 0.0435 R₁ = 0.0746 R₁ = 0.0388 R₁= 0.0333 [I > 2σ(I)] wR₂ = 0.0968 wR₂ = 0.1967 wR₂ = 0.0863 wR₂ = 0.0789R indices (all data) R₁ = 0.0668 R₁ = 0.0746 R₁ = 0.0684 R₁ = 0.0517 wR₂= 0.1051 wR₂ = 0.1967 wR₂ = 0.1036 wR₂ = 0.0848 Largest diff peak 2.561and −0.561 2.845 and −2.384 2.074 and −1.089 1.766 and −0.876 and hole(e/Å³)

Results and Discussion

A detailed description of a synthesis of the ligands has been reportedpreviously in a combinatorial solution method for their synthesis. Usinga method based on this earlier synthesis, the fluorescent yellow2-quinoxolinol salen ligands were obtained as solids in high yield. Theligands were bright yellow in color, stable in air, and soluble in arange of organic solvents. The uranyl complexes have been obtained bycombining the appropriate Schiff base with hexa-hydrated UO₂(OAc)₂ in a(50:50) solution of dichloromethane and methanol resulting in reddishbrown precipitates. Complexes of the ligand H₂L4 with transition metalscould be obtained in quantitative yields with longer periods of heat orwith the addition of base.

Crystals of the UO₂L1.DMF were grown by solvent diffusion of the metalcomplex in dimethyl formamide with ether. The crystals formed as darkred acicular prisms, conforming to space group C2/c with Z=4. Thegeneral coordination motif of uranyl-Schiff base complexes is similar tothat seen in the uranyl (UO₂ ²⁺) salophen(N,N′-disalicylidene-o-phenylenediaminate) complexes having apentagonal-bipyramidal geometry with the equatorial plane of the uranylion coordinated by the two oxo- and two aza-coordination sites of theligand and the fifth position in that plane occupied by a DMF solventmolecule. This was typical with what was seen in this series of ligands.

The 2-quinoxalinol salen ligands demonstrate a significant twist uponcoordination of a metal. This can be seen in the side view of the metalcomplex (data not shown) This is more pronounced than the 35° seen inthe salophen uranyl complex, close to 45° from the coordination plane ofthe metal ion indicating a strongly bound complex. The average U—N bonddistance in the coordination core is 2.55(3) Å, and the average U—O bonddistance is 2.25(5) Å. These bond distances are comparable to thesalophen uranyl complexes reported previously (data not shown)

A uranyl complex of ligand UO₂L4.H₂O was prepared to demonstrate asecond crystallization method using the ligand with improved organicsolubility. Such a system might be more suitable in extractionapplications. Crystals of the uranyl complex of ligand UO₂L4.H₂O weregrown from a solution of the ligand in acetone layered with an aqueoussolution of uranyl acetate. This serves to demonstrate the strongcoordination capability of the ligand specific to the uranyl ion.Crystals formed as red needles at the interface of the two layers,conforming to space group P2₁/n with Z=4. The asymmetric unit cellcontains two independent, seven-coordinate uranyl complexes that differin the conformation of the ligand substituents. This results in anoticeable difference in the bond distances despite similar environmentaround uranium center (Table 7). Each complex has one ligandcoordinating the metal ion and the fifth coordination site occupied by awater molecule. The U—O bond distances in the “yl” oxygens are typicalfor uranyl complexes, averaging 1.78(2) Å. The angles of the O—U—O ofthe uranyl metal ions are near linear at 177.6(10)° for U1 and 178.51(11)° for U2. The average bite angle of the N—U—O angle is 68.9(3)°. Theaverage U—N and U—O bond distances in the coordination core of the twomolecules are very similar to that seen before, 2.56(4) Å and 2.25(2) Å,respectively.

Spectroscopy

In the ¹H NMR spectra of the uranyl (UO₂ ²⁺) complexes, a significantshift in the imine CH═N proton is observed in the uranyl metal complexes(9.6-9.8 ppm for L1-L3, 9.2-9.3 ppm for L4) as compared to the freeligands (8.9-9.3 ppm). (This difference in L4 is presumably due to thedifference in solvation.) This is indicative of the imine nitrogen lonepairs coordinating to the metal center. In a similar fashion, there arethree hydroxyl peaks in the ¹H NMR spectra of the free ligands(12.1-13.3 ppm) while in the uranyl (UO₂ ²⁺) complexes, only one fromthe quinoxolinol hydroxyl group remains (12.6-12.7 ppm for L1-L3, 12.2ppm for L4).

In the IR spectra of UO₂L1.DMF, UO₂L2.DMF, and UO₂L4.H₂O have strongpeaks around 1620 cm⁻¹ (free ligands 1654-1658 cm⁻¹) indicatingcoordinated imine nitrogens. The uranyl complex of ligand UO₂L3.DMF hasa strong vibration at 1603 cm⁻¹ (free ligand 1658 cm⁻¹) indicatingcoordinated imine nitrogens. This slight difference between UO₂L1.DMF,UO₂L2.DMF and UO₂L3.DMF may be the result of the absence of the phenylgroup in the quinoxolinol backbone. Coordination through the phenolichydroxyl unit in the salicylaldehyde coordination site can also be shownby the shift in the C—O band for uranyl complexes of ligands UO₂L1.DMFand UO₂L2.DMF (1203 cm⁻¹) as compared to the free ligands (1276 and 1271cm⁻¹, respectively). This is also seen in UO₂L3.DMF and UO₂L4.H₂O,although it is shifted slightly from the other ligands with bands at1263 cm⁻¹ and 1229 cm⁻¹ respectively compared to the free ligands (H₂L3,1278 and H₂L4, 1261 cm⁻¹). Bands around 900 cm⁻¹ seen in the uranylcomplexes are due to the asymmetric and symmetric UO₂ stretchingcharacteristic of linear uranyl ion in the complex.

Broad peaks in free ligands seen around 3400 cm⁻¹ (3392-3448 cm⁻¹) areindicative of the presence of the hydroxyl groups. These are seen to beabsent in the Cu, Co, Ni, and Mn, metal complexes of ligand H₂L4,presumably indicating the formation of metal complex with these oxygens.This coordination can be confirmed using the shift in the C—O band ofthe hydroxy unit in the salen coordination site for the transition metalcomplexes of ligand H₂L4, Co (1256 cm⁻¹), Cu (1260 cm⁻¹), Ni (1260 cm⁻¹)and Mn (1248 cm⁻¹), compared to the free ligand, H₂L4 (1261 cm⁻¹). Thisis also seen in bands indicative of binding to the lone pairs of theimine nitrogens in the complexes of H₂L4 with Co (1614 cm⁻¹) and Ni(1616 cm⁻¹) compared to the free ligand (1656 cm⁻¹).

Table 7. Selected interatomic distances (Å) and angles (°) for uranylcomplexes UO₂L1.DIMF, UO₂L2.DMF. UO₂L3.DMF. and UO₂L4.H₂O (*UO₂L49H₂Ouses molecule 1 of the dimolecular unit cell.)

(UO₂)L1•(DMF) (UO₂)L2•(DMF) U1—O1 2.241(4) O1—U1—N1 70.57(2) U1—O32.233(8) O3—U1—N1 70.1(3) U1—O2 2.250(4) O2—U1—N2 69.38(1) U1—O42.239(9) O4—U1—N2 71.3(3) U1—O3 2.400(4) O4—U1—O5 176.71(2)  U1—O1O12.415(9) O1—U1—O2 176.71(2)  U1—N1 2.521(4) N1—U1—N2 62.83(1) U1—N1 2.571(10) N1—U1—N2 63.6(3) U1—N2 2.582(4) O1—U1—O4 93.03(2) U1—N22.528(9) O2—U1—O3 93.0(4) U1—O4 1.782(4) O2—U1—O4 92.37(2) U1—O11.800(9) O2—U1—O4 92.9(4) U1—O5 1.796(4) U1—O2 1.786(8) (UO₂)L3•(DMF)(UO₂)L4•(H₂O) U1—O1 2.252(4) O1—U1—N1 69.96(2) U1—O3 2.254(2) O3—U1—N169.23(9)  U1—O2 2.259(4) O2—U1—N2 69.75(2) U1—O4 2.255(2) O4—U1—N268.71(8)  U1—O5 2.375(5) O4—U1—O3 176.15(2)  U1—O5 2.456(2) O1—U1—O2177.62(10)  U1—N1 2.549(5) N1—U1—N2 63.28(2) U1—N1 2.551(3) N1—U1—N263.54(8)  U1—N2 2.571(4) O1—U1—03 87.57(2) U1—N2 2.577(3) O1—U1—0491.67(9)  U1—O3 1.805(4) O2—U1—03 86.76(2) U1—O1 1.774(2) O2—U1—0487.38(10) U1—O4 1.782(4) U1—O2 1.779(2)

In DMF, ligand H₂L1 features two UV peaks at 305 nm (δ=32000) and 390 nm(δ=32000). (Data not shown.) The addition of an aqueous solution of HClcauses (3-fold excess) a slight shift to 300 nm and 390 nm with nochange seen in the extinction coefficients, Upon the addition of theuranyl ion (UO₂ ²⁺), as a solution of uranyl acetate, the absorptionmaximum in the UV-Vis spectra demonstrates a shift to 290 nm (∈=20000)and 370 nm (∈=15000) with an additional peak at 440 nm (∈=1 5000),indicating the formation of uranyl complex. Similar bands have beenreported for multidentate hydroxyl-containing uranyl complexes (390 and450 nm). A similar shift is seen in the spectra in addition to theformation of additional peaks are seen in the uranyl complex UO₂L3.DMF(336 nm, 388 nm). The uranyl complex UO₂L3.DMF features additional peakswith maxima at 287 nm (∈=1.7×10⁴), 304 nm (∈=1.6×10⁴), 360 nm(∈=1.3×10⁴),385 nm (∈=1.3×10⁴), and 419 nm (∈=1.4×10⁴). The UO₂L4.H₂Ocomplex in DMF also demonstrated a shift due to the formation of metalcomplex with maximum absorbances at 295 nm (∈=2.5×10⁴), 375 nm(∈=1.6×10⁴), and 440 nm (∈=1.5×10⁴). This was found to be significantlydifferent than the copper complex of the same ligand in DMF, CuL4: 280nm (∈=3.4×10⁴), 325 nm (∈=2.8×10⁴), and 454 nm (∈=1.5×10⁴).

TABLE 8 Extinction Coefficients for metal complexes of ligand 4 indichloromethane. Metal Ion Extinction Metal Ion Extinction (MaxWavelength) Coefficient (Max Wavelength) Coefficient Free ligand (301nm) 44500 Cobalt (437 nm) 69000 Free ligand (391 nm) 44100 Cobalt (322nm) 60000 Manganese (510 nm) 71000 Copper (458 nm) 92000 Manganese (372nm) 40000 Copper (330 nm) 76000 Nickel (452 nm) 91000 Copper (286 nm)62000 Nickel (388 nm) 57000 Uranyl (250 nm) 34000 Nickel (314 nm) 48000Uranyl (300 nm) 29000 Nickel (268 nm) 46000 Uranyl (379 nm) 24000 Uranyl(456 nm) 17000

Because of spectral changes due to the effects of solvent and fromligand to ligand, in order to have a better comparison between uranyland other potentially competing metals, the transition metal complexesof ligand 4 were prepared along with the uranyl complex indichloromethane for UV-Vis spectroscopy. The results are shown in Table8. (See spectra S2-S7 in Supplementary material.) The different metalcomplexes can be distinguished by their distinct spectra. Thedifferences between the spectra seen in the coordinating solvent DMF andthe non-coordinating DCM, are due to the fact that the fifthcoordination site in the plane of the uranyl is not filled by solvent,possibly leading to dimers. The cobalt complex has two intense peaks at322 nm (∈=6.0×10⁴) and 437 nm (∈=6.9×10⁴). The copper complexdemonstrated the most intense peaks with the highest extinctioncoefficients at 330 nm (∈=7.6×10⁴) and 458 nm (∈=9.2×10⁴) and anadditional peak at 286 nm (∈=6.2×10⁴). The manganese complexdemonstrated two intense peaks at 372 nm (∈=4.0×10⁴) and 510 nm(∈=7.1×10⁴), and so could be distinguished by the unique peak at 510 nm.The nickel complex had four peaks with one very close to the 458 nm ofcopper at 452 nm (∈=9.1×10⁴), but could be distinguished from copper bythe additional peaks at 388 nm (∈=5.7×10⁴), 314 nm (∈=4.8×10⁴) and 268nm (∈=4.6×10⁴). Finally, the uranyl in dichloromethane is unique withtwo shoulders at 379 nm (∈=2.4×10⁴) and 456 nm (∈=1.7×10⁴) resultingfrom the metal complex and peaks at 250 nm (, =3.4×10⁴) and 300 nm(∈=2.9×10⁴).

Lanthanide complexes with salen ligands have been described; however,often it has been found the metal is coordinated only to the oxo-groupsof the ligand, resulting in a coordination polymer or a sandwichcomplex. Complexes that can be formed without protection from air ormoisture are particularly useful. Without using inert atmosphere methodsof preparing air sensitive complexes, these ligands did not demonstratecomplex formation with lanthanides either with heating or with theaddition of strong base with lanthanide chloride, acetate, oracetoacetonate salts (as judged by UV-Vis or NMR). This is indicative ofa certain amount of selectivity for the actinides, based on the highoxophilicity typical of the lanthanides as compared to the actinideswhich tend to demonstrate more covalent character in their bonding. Thisis consistent with the high oxophilicity of the lanthanides. Lanthanidesgreatly prefer hard interactions and an all oxo-coordinating systemwhile actinides will also bind to the nitrogen heteroatoms. Since at thebottom of the periodic table, there are very small differences in ionicradii between metals, separating the lanthanides produced as daughterproducts during the nuclear fuel cycles is quite a challenge. Thisdifference in their chemistry has been exploited in the development ofsulphur or phosphorus containing ligands—such as CMPO(octyl(phenyl)-N,N-diisobutylcarbamoyl methylphosphine oxide)—for theseparation and isolation of the actinides. This will require furtherinvestigations to elucidate selectivity and determine the potentialutility of these ligands in separations applications.

Conclusions

The 2-quinoxolinol Schiff base ligands and their uranyl-complexes havebeen synthesized and characterized. Crystal structures demonstratepentagonal bipyramidal geometry around uranium center with the 2 aza and2 oxo coordinating sites of the ligand perpendicular to the “-yl”oxygens. The remaining coordination site of the metal is occupied by asolvent molecule. A significant twist of the ligand from planar is seento occur upon coordination of a metal. This results in a change in theπ-orbital overlap of the ligand backbone and contributes to a dramaticchange in the ultraviolet-visible spectrum. The use of non-coordinatingsolvents results in the formation of ligand dimers. The presence ofdifferent substituents on the salicylaldehyde moiety incorporated intothe ligand backbone affects the solubility of the ligand greatly andalso affects the response seen through spectroscopy.

Combining oxo- and imine aza-coordination sites as used here, has beendemonstrated to impart a degree of selectivity for uranyl in particularover lanthanides. At elevated temperature, the ligand has been found toform stable complexes with Cu, Ni, Co, and Mn. Characterization of thetransition metal complexes demonstrates that while the uranyl complex ismore easily formed, when other metal complexes are formed theirspectroscopic signature is characteristic to discriminate between uranyland transition metals. While possesing a strong signal uponcoordination, solubility complicates the determination of selectivity.The change in the UV-Vis spectra of the uranyl complex as compared totransition metal complexes, in partcular Cu²⁺, may be exploited in thedevelopment of sensors for actinides on surfaces or in contaminatedareas.

Additional experiments to develop these ligands as selective metalcoordination systems for use in sensors or extraction applications willcontinue with experiments to quantify selectivity for uranium oractinides over lanthanides and with experiments probing fluorimetricmethods to increase sensitivity. The use of fluorimetry would be anotherway to rule out competition from transition metals in sensing ofactinides. These investigations will broaden an understanding of thechemical behavior of the actinides and enable the development of newsensors and sensing materials for improved detection and isolation ofactinides from fuel wastes or contaminated environmental sites.

Example 3 References

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Example 4

Reference is made to Wu et al., “One-Pot Metal Templated Synthesis forthe Preparation of 2-Quinoxalinol Salen Metal Complexes,” Polyhedron,Volume 28, Issue 2, 3 Feb. 2009, Pages 360-362, the content of which isincorporated herein by reference in its entirety.

Abstract

Metal complexes of 2-quinoxalinol salen (salqu) ligands can be preparedin a one-pot metal templated synthesis resulting in significantlyenhanced yields than if the ligand were prepared and isolated prior tointroducing the metal for complexation. Using this method, 12 salqumetal complexes have been prepared and characterized from +2 metal ions.

One-pot multicomponent syntheses have received increasing attention oflate, because they not only address fundamental principles of syntheticefficiency and reaction design, but they also expand the possibilitiesfor extending one-pot reactions into combinatorial and solid-phasemethods. This presents a new way of thinking about “greener” chemistryby allowing for the reduction of synthetic steps, purification solvents,and wastes. A one-pot metal templated strategy for the preparation ofmetal complexes for use in applications offers the distinct advantagesof reduced environmental impacts and easier procedures for workup.

Salen or salph complexes have been used widely in applications foreverything from catalysts to molecular recognition. For example, salenCu, Mn, or Ru complexes have been used as catalysts in the catalyticoxidation of secondary amines, as the basis for enantioselectivecatalysts, and as catalysts for ring-opening metathesis. Uranyl (UO₂ ²⁺)salophen complexes have been used in molecular recognition studies. Inaddition, salen Mn complexes can act as catalytic scavengers of hydrogenperoxide and have been demonstrated to have a degree ofcytoprotectivity.

Symmetric and asymmetric 2-quinoxolinol salen ligands (abbreviatedsalqu, e.g. 3) have been synthesized for use in catalysis using solutionphase and combinatorial strategies. A disadvantage of this reactionscheme was an extended reaction time required to obtain the optimalyields. Metal complexes of this series of ligands were then prepared bya standard proton transfer procedure. Because applications in solidphase extraction and catalysts of salqu metal complexes have beendiscovered, it was thought that it would to be advantageous to find amore efficient, economical method to prepare salqu metal complexes.Here, a one-pot synthetic method based on a metal template synthesis toaccess salqu metal complexes will be introduced. With this method, 12salqu metal complexes have been synthesized from diamino-2-quinoxalinol(1, Scheme 7) in significantly higher yields in a shorter time than whenthe ligand is isolated and purified prior to complexation.

Previously, to prepare the salqu metal complexes, two steps wererequired. The first being the preparation of salqu ligands followed bypreparation of the salqu metal complex. In the synthesis of symmetricsalqu ligands, the final optimized conditions required that thediamino-2-quinoxalinol intermediate 1 be reacted with 10 equivalents ofthe desired salicylaldhyde derivatives (2) at reflux temperature inmethanol for 48 hours. The ligand must then be isolated prior to theaddition of the metal to prepare the metal complex, resulting in yieldsaround 60.0%. Metal complexes are then prepared from a reaction of thesalqu ligand (3) with 1.2 equivalents of the desired metal acetate atreflux temperature in either DMF or DCM with MeOH reacted for 2-12hours. The final yields for this step are around 85.0%, resulting in anoverall yield for both reactions close to 50%.

Using a metal templating strategy for a one-pot synthetic method, thediamino-2-quinoxalinol intermediate 1 was reacted with only 2.1equivalents of the salicylaldhyde derivative (2) and 1.1 equivalents ofmetal acetate were added directly to the reaction mixture. This alsodoes not require a mixed solvent system, and only methanol was used. Themixture was then heated to reflux temperature and allowed to react for 6hours. After the reaction was determined to be complete, a largequantity of red or black solid was found to precipitate from solution.The precipiates were filtered and washed with ethanol for 5 times. Thesolids were dried to obtain salqu metal complexes with purity greaterthan 95% (Purity was identified by NMR and TLC.) Yields were found torange from 60-85%. The results are listed in Table 9.

TABLE 9 Salqu metal complexes synthesized using a one-pot metaltemplated method. [M]²⁺ R₁ R₂ Yield 3a Cu²⁺

3,5-di-tert-butyl 72.8 3b Cu²⁺

H 80.0 3c Mn²⁺

3,5-di-tert-butyl 76.5 3d Co²⁺

3,5-di-tert-butyl 69.4 3e Ni²⁺

3,5-di-tert-butyl 62.7 3f UO₂ ²⁺

3-OH 84.5 3g UO₂ ²⁺

3,5-di-tert-butyl 62.0 3h UO₂ ²⁺

H 61.2 3i UO₂ ²⁺

3,5-di-tert-butyl 65.3 3j UO₂ ²⁺

H 63.4 3k UO₂ ²⁺

H 67.0 3l UO₂ ²⁺

H 69.8

The IR spectral results are indicative of metal complexation. Broadpeaks in free ligands seen around 3400 cm⁻¹ (3400-3448 cm⁻¹) areindicative of the presence of the hydroxyl groups on the free ligand.These broad signals are seen to be absent in the Cu, Mn, Co, Ni, and UO₂metal complexes indicating the formation of the metal complex with theseoxygens. Coordination through the phenolic hydroxyl unit in thesalicylaldehyde coordination site can also be shown a shift in the C—Oband for the metal complexes between 1199-1213 cm⁻¹ as compared to thesharp peak in the free ligands (1263-1276 cm⁻¹). (3j was lower 1146 cm⁻¹although there was not a peak seen as in the range characteristic of theC—O stretch in the starting material.)

The spectra of the free ligands have peaks around 1654-1658 cm⁻¹ for thecarbon-nitrogen imine stretch. This was seen to shift to 1599-1620 cm⁻¹(3f-3l) for the uranyl complexes and was indicative of coordinated iminenitrogens. This peak was seen at 1616-1614 cm⁻¹ in the Ni²⁺ and Co²⁺complexes, and in the Cu²⁺ complex (3b) but was not as well defined inthe Mn²⁺ or in the Cu²⁺ (3a) in which the metal may not be stronglycoordinating to the imines. Bands around 900 cm⁻¹ (897-903 cm⁻¹) seen inthe uranyl complexes (3f-3l) are due to the asymmetric and symmetric UO₂stretching characteristic of linear uranyl ion in the complex.

In the ¹H NMR spectra of the uranyl (UO₂ ²⁺) complexes, a significantshift in the imine CH═N proton was observed in the uranyl metalcomplexes (9.5-9.8 ppm for 3f-3l) as compared to the free ligands(8.9-9.3 ppm). This was indicative of the imine nitrogen lone pairscoordinating to the metal center. In a similar fashion, there are threehydroxyl peaks in the ¹H NMR spectra of the free ligands (12.1-13.3 ppm)while in the uranyl (UO₂ ²⁺) complexes, only one from the quinoxolinolhydroxyl group remains (12.6-12.7 ppm for 3f, 3h, and 3j-3l, 12.2-12.3ppm for 3g, 3i).

The advantages of the one-pot synthetic method for preparing salqu metalcomplexes are the shortened reaction time from more than 2 days to 6hours and improved final yields from less than 50.0% to over 60-85%.This permits optimization of the procedure in order to conserve theamounts of the salicylaldhyde derivatives (2) used while avoiding usingthe more troublesome solvent DMF. This method could be incorporated intoa combinatorial method for synthesis of these complexes because of itsrelative simplicity and high yield.

In conclusion, a one-pot methodology based on a metal templatingsynthesis using +2 metal ions to more easily and rapidly prepare salqumetal complexes is an efficient method to prepare these metal complexes.With this method, several salqu metal complexes have been synthesizedand identified. This will be a more convenient synthetic method inexploring the use of such metal complexes. In the future, a new salqumetal complex library will be prepared in this way.

General Procedure and Data

All amino acid methyl esters, DFDNB, HCl (37%) and aldehydes werepurchased from Acros Organics Co. Ammonium hydroxide (5.0 N), palladiumon carbon (wet, 5%) were purchased from Sigma-Aldrich Co. Startingmaterials were used as received. All organic solvents were purchasedfrom Thermo Fisher Scientific Co. and were used directly for synthesis.¹H and ¹³C NMR spectra were recorded on Bruker AC 250 spectrometer(operated at 250 and 62.5 MHz, respectively) or Bruker AV 400spectrometer (operated at 400 and 100 MHz, respectively). Chemicalshifts are reported as 6 values (ppm). The solvents used are indicted inthe experimental details. Electrospray ionization mass spectrometry wasperformed on a Micromass QTOF mass spectrometer (Waters Corp, MilfordMass.). Direct probe samples were on a VG-70S mass spectrometer (WatersCorp, Milford Mass.). Reaction progress was monitored by thin-layerchromatography (TLC) using 0.25 mm Whatman Aluminum silica gel 60-F254precoated plates with visualization by irradiation with a MineralightUVGL-25 lamp. IR spectroscopic data was collected using a Shimsdzu™ Inc.IR, Prestige-21 Fourier Transform Infrared Spectrophotometer and KBrsolid samples.

To a 5 ml methanol solution of intermediate 1 (0.05 mmol), 2.1equivalents of the desired salicylaldehyde derivatives (e.g., 2 0.105mmol) and 1.1 equivalent of metal acetate (0.055 mmol) were added. Themixture was heated to reflux temperature with stirring and allowed toreact for 6 hours. At this time, a dark red or black solid precipitatesout, indicating the completion of the reaction. The precipitates werefiltered from the reaction solution. They were then washed with ethanolfive times. Finally, the solids were dried under high vacuum.

3a IR: 3067, 2955, 1661, 1586, 1528, 1491, 1416, 1377, 1260, 1209, 1173,1130 cm⁻¹. MS: 760.0 (M+H); HRMS: found (760.3413); calc (760.3422).

3b IR: 3510, 3392, 1655, 1605, 1587, 1560, 1526, 1499, 1442, 1382, 1331,1200, 1178, 1151. cm⁻¹. MS: 536.1 (M+H); HRMS: found (536.0912); calc(536.0909).

3c IR: 3385, 3248, 3208, 2955, 2911, 1670, 1582, 1532, 1462, 1416, 1317,1248, 1177, 1130 cm⁻¹. MS: 751.3 (M+H); HRMS: found (751.3420); calc(751.3429).

3d IR: 3066, 2957, 1665, 1614, 1572, 1524, 1501, 1462, 1410, 1256, 1180,1128 cm⁻¹. MS: 755.3 (M+H); HRMS: found (755.3369); calc (755.3372).

3e IR: 3067, 2955, 2870, 1665, 1616, 1584, 1533, 1598, 1464, 1414, 1379,1260, 1182, 1130 cm⁻¹. MS: 755.3 (M+H); HRMS: found (755.3461); calc755.3471.

3f ¹H-NMR (400 MHz DMSO-d⁶): δ 4.22 (s, 2H), 6.54-8.67 (m, 13H), 9.55(s, 1H), 9.71 (s, 1H), 11.77 (bs, 1H), 11.82 (bs, 1H), 12.69 (bs, 1H).¹³C-NMR: 160.2, 159.4, 155.0, 137.8, 132.8, 132.0, 129.7, 128.9, 126.9,126.3, 124.1, 124.0, 123.9, 119.5, 117.1, 106.3, 42.0. IR: 3397, 3337,2965, 1657, 1620, 1582, 1545, 1491, 1445, 1204, 903 cm⁻¹. MS: 816.2(M+H+CH₃CN); HRMS: found (816.2178); cal (816.2183).

3g ¹H-NMR (400 MHz DMSO-d6): δ 1.19 (s, 18H), 1.64 (s, 18H), 4.11 (s,2H), 7.09-7.63 (m, 10H), 7.70 (s, 1H), 9.19 (s, 1H), 9.32 (s, 1H), 12.18(bs, 1H). ¹³C-NMR: 173.3, 173.0, 171.2, 165.1, 153.8, 148.8, 144.6,144.3, 143.5, 142.0, 137.1, 135.9, 134.2, 133.1, 131.3, 128.9, 123.3,110.6, 42.0, 40.3, 38.6, 36.3, 35.1. IR: 3433, 2957, 1655, 1620, 1383,1283, 1229, 1153, 937, 760 cm⁻¹. MS: 967.4 (M+H); HRMS: found(967.4514); calc (967.4524).

3h ¹H-NMR (400 MHz DMSO-d⁶): δ 4.20 (s, 2H), 6.73-6.77 (t, 2H),7.00-7.04 (t, 2H), 7.24-7.88 (m, 10H), 8.12 (s, 1H), 9.60 (s, 1H), 9.76(s, 1H), 12.67 (bs, 1H). ¹³C-NMR: 170.8, 170.2, 168.0, 167.3, 161.3,155.0, 148.9, 143.6, 137.8, 137.3, 136.5, 132.8, 129.7, 128.9, 126.9,124.8, 121.4, 121.0, 119.5, 117.4, 106.3, 42.3. IR: 3397, 3337, 2965,1657, 1620, 1582, 1545, 1491, 1445, 1204, 1144, 1040 cm⁻¹. MS: 784.0(M+H+CH₃CN); HRMS: found (784.2280); calc (784.2285).

3i ¹H-NMR (400 MHz DMSO-d⁶): δ 1.22 (d, 6H), 1.26 (s, 18H), 1.69 (s,18H), 3.50 (m, 1H), 7.26-7.80 (m, 6H), 9.30 (s, 1H), 9.46 (s, 1H), 12.28(bs, 1H). ¹³C-NMR: 173.3, 172.6, 153.4, 148.6, 144.6, 144.4, 143.3,136.8, 135.7, 134.4, 128.9, 123.3, 110.4, 40.4, 38.6, 36.4, 35.1, 25.1.IR: 3444, 2958, 1710, 1666, 1587, 1423, 1371, 1224, 898 cm⁻¹. MS: 919.2(M+H); HRMS: found (919.4514); calc (919.4524).

3j ¹H-NMR (400 MHz DMSO-d⁶): δ 1.28 (d, 6H), 3.56 (m, 1H), 6.74-8.17 (m,10H), 9.61 (s, 1H), 9.81 (s, 1H), 12.58 (bs, 1H). ¹³C-NMR: 170.8, 170.2,170.0, 167.9, 166.6, 154.6, 148.3, 143.5, 137.2, 136.5, 132.5, 131.9,124.8, 124.6, 121.4, 121.0, 119.4, 117.4, 106.2, 30.5, 20.6. IR: 3406,2966, 1654, 1602, 1539, 1463, 1400, 1384, 1145, 898 cm⁻¹. MS: 736.2(M+H); HRMS: found (736.2280); calc (736.2285).

3k ¹H-NMR (400 MHz DMSO-d⁶): δ 1.00 (d, 6H), 2.28 (m, 1H), 2.74 (d, 2H),6.75 (t, 2H), 7.03 (t, 2H), 7.44 (s, 1H), 7.65 (m, 2H), 7.87 (t, 2H),8.19 (s, 1H), 9.61 (s, 1H), 9.78 (s, 1H), 12.54 (bs, 1H). ¹³C-NMR:170.8, 170.2, 162.3, 155.2, 148.3, 143.4, 137.2, 136.5, 132.6, 132.0,124.8, 124.6, 121.4, 121.1, 119.3, 117.4, 106.2, 42.1, 26.8, 23.1. IR:3395, 2927, 1637, 1606, 1539, 1463, 1435, 1383, 1282, 937 cm⁻¹. MS:709.2 (M+H); HRMS: found (709.2167); calc (709.2176).

3l ¹H-NMR (400 MHz DMSO-d⁶): δ 2.15 (s, 3H), 2.96 (t, 2H), 3.16 (t, 2H),6.75 (t, 2H), 7.03 (t, 2H), 7.46 (s, 1H), 7.66 (m, 2H), 7.87 (t, 2H),8.19 (s, 1H), 9.62 (s, 1H), 9.78 (s, 1H), 12.64 (bs, 1H).). ¹³C-NMR:170.8, 170.2, 168.0, 167.2, 161.1, 155.0, 148.5, 143.5, 137.3, 136.5,132.7, 131.2, 124.7, 121.4, 121.0, 119.4, 117.5, 106.3, 33.3, 30.5,15.2. IR: 3395, 2927, 1637, 1606, 1539, 1463, 1435, 1383, 1282, 937cm⁻¹. IR: 3408, 1655, 1637, 1601, 1583, 1537, 1464, 1440, 1382, 1300,1199, 1150, 897, 760 cm⁻¹. MS: 768.2 (M+H); HRMS: found (768.2013); calc(768.2006).

Example 4 References

-   1. Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000, 37,    647.-   2. Posner, G. H. Chem. Rev. 1986, 86, 831.-   3. Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366.-   4. Kobayashi, S. Chem. Soc. Rev. 1999, 28, 1.-   5. Murahashi, S.; Naota T.; Taki, H. J. Chem. Soc., Chem. Commun.,    1985, 613.-   6. Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am.    Chem. Soc., 1990, 112, 2801.-   7. Wu, M. H.; Hansen K. B.; Jacobsen, E. N. Angew. Chem., Int. Ed.    1999, 38, 2012.-   8. Reinoso-Garcia, M. M.; Dijkman, A.; Verboom, W.; Reinhoudt, D.    N.; Malinowska, E.; Wojciechowska, D.; Pietrzak M.; Selucky, P.    Eur. J. Org. Chem. 2005, 2131.-   9. Van Axel Castelli, V.; Dalla Cort, A.; Mandolini, L.; Pinto, V.;    Reinhoudt, D. N.; Ribaudo, F.; Sanna, C.; Schiaffino, L.;    Snellinkruel, B. H. M. Supramolecular Chem. 2002, 14, 211.-   10. Rudkevich, D. M.; Stauthamer, W. P. R. V.; Verboom, W.;    Engbersen, J. F. J.; Harkema, S.; Reinhoudt, D. N. J. Am. Chem. Soc,    1992, 114, 9671.-   11. Doctrow, S. R.; Huffman, K.; Marcus, C. B.; Tocco, G.; Malfroy,    E.; Adinolfi, C. A.; Kruk, H.; Baker, K.; Lazarowych, N.;    Mascarenhas, J.; Malfroy, B., J. Med. Chem. 2002, 45,-   12. Wu, X.; Gorden, A. E. V. J. Comb. Chem. 2007, 9, 601.-   13. Wu, X.; Gorden, A. E. V.; Tonks, S. A.; Vilseck, J. Z. J. Org.    Chem. 2007, 72, 8691.-   14. Wu, X.; Bray, T. H.; Bharara, M.; Tate, B. K.; Gorden, A. E. V.    Inorg. Chim. Acta. 2008, in press.-   15. Wu, X.; Gorden, A. E. V. Tetrahedron Lett. 2008, 49, 5200.-   16. Wu, X.; Gorden, A. E. V. Eur. J. Org. Chem. accepted-   17. Casellato, U.; Tamburini, S.; Tomasin, P.; Vigato, P. A. Inorg.    Chim. Acta. 2002, 341, 118.-   18. Abu-Hussen, A. A. J. Coord. Chem. 2006, 59, 157.

Example 5

Wu et al., “2-Quinoxalinol Salen Ligands Incorporated IntoFunctionalized Resins for Selective Solid-Phase Extraction of Copper(II),” Tetrahedron Letters, Volume 49, Issue 35, 25 Aug. 2008, Pages5200-5203, the content of which is incorporated herein by reference inits entirety.

Abstract

In exploring selective extraction systems for use in environmentalremediation or in metal scavenging agents for use in combinatorialchemistry, a novel reagent for the selective extraction of copper (II)has been developed. 2-Quinoxalinol salen ligands supported on anaminomethyl-polystyrene resin has been shown to efficiently andselectively extract copper (II) ions from organic solvents within 30minutes under a variety of experimental conditions. Mild reducingconditions allow for metal ion recovery.

Solid-phase extraction (SPE) technologies are being used in a widenumber of areas including environmental chemistry, medicinal chemistry,combinatorial chemistry, agriculture, and food science. This technologyhas been used in environmental applications to monitor or extract toxicheavy metal cations such as Hg²⁺, Pb²⁺, As³⁺, etc. Others have appliedsolid phase micro-extraction (SPME) techniques to analyze biologicalfluids in diagnostic medicine. In food science, SPE technologies areused extensively in food analysis and quality control. Currently themost common application of SPE technology currently in use is in theidentification of drug components, one promising area of SPE technologynot as widely investigated is as a scavenging agent to remove excesscatalysts or metal ions used in synthetic methods or combinatorialchemistry.

Copper salts are often applied as catalysts in a variety of organicsynthetic procedures. An overabundance of copper in the environment isof concern due to possible harmful effects to agriculture, fish, orwildlife. SPE technology for the selective recovery of copper has notpreviously been described in the literature. Such technology hasconsiderable potential and would allow many catalytic or couplingreactions commonly used in the synthetic laboratory to be moreaccessible for use in combinatorial processes or in industrialapplications where excess or trace metal ions are likely to complicatesubsequent reactions. In addition, because of the high cost of copperreagents, this would create a more efficient and more readily recyclablesystem thereby limiting the need for costly copper reagents.

In previous research, both symmetric and asymmetric 2-quinoxalinol salenligands were prepared. (See structure 1 as an example). It has beenfound that these ligands can coordinate +2 metal cations. Detailed hereare methods of preparing solid phase reagents comprising 2-quinoxalinolsalen ligands and their application in the selective extraction andrecovery of copper cations.

Polystyrene (PS) aminomethyl resin was selected as solid carrier,because this resin can swell in many organic solvents. Glutaricanhydride was selected as linker between solid carrier and2-quinoxalinol salen ligand. The isopropyl-2-quinoxalinol salen ligand(1) was selected as the coordination ligand, both because the5′-hydroxyl group on the outer portion of the salen is a convenient sitefor incorporating the resin, and because its yield is the highest of thesymmetric library. Presented in Scheme 8 is the optimized method for thesynthesis of solid reagents PLG1 or PLG2.

Different molar ratios and various solvents were investigated tooptimize the acylation of the amino group onto the (PS) aminomethylresin. Finally, a molar ratio of glutaric anhydride to (PS) aminomethylresin 5:1 using dichloromethane as solvent at room temperature for 24hours was found to be the optimum conditions for acylation of the aminogroup. After acylation was completed, the resin was washed with DCM,DMF, and MeOH, three times each. The loaded resin PL can be furtheracylated with 1.5 equivalent of ligand 1 by using 2.2 equivalents of4-dimethyl-aminopyridine (DMAP) and 2.2 equivalents ofN,N′-diisopropyl-carbodiimide (DIC) in distilled, dry DMF at roomtemperature for three days. Extending the reaction time does notincrease loading. Without DMAP, the loading was very low. If wet DMF wasused, the loading capability was decreased, because DIC can bedecomposed easily by moisture.

There are three potential binding sites (the 2, 2′ and 5′ positions) forthe carboxylic acid linker to attach to ligand 1. Positions 2 and 2′cannot react with the carboxylic acid moiety due to reactive inertia of2 position and bonding also limits the reactivity of the hydroxyl groupon the 2′ position. Reaction with hydroxyl groups in the two 5′positions, results in two possible products (i.e., PLG1 and PLG2). Theyhave the same coordination capability to bind +2 valence metal cationsbecause the salen coordination cavity is not affected by their position.By this procedure, PL was obtained with 100.0% loading by ninhydrin testand PLG1 and PLG2 were obtained with 60.0-65.0% loading, as determinedby mass. Identification of resins PLG1 and PLG2 was made by comparingthe major peaks of an IR spectra ofligand 1 (3381.2, 1658.8, 1622.3,1577.8, 1489.1, 1278.8 cm⁻¹).

With this solid ligand functionalized reagent in hand, extractionstudies were run in several different solvent combinations: DMF,DMF/MeOH, MeOH, THF/MeOH, steric hindrance of the 2′ position. HydrogenDCM/MeOH and DCM/EtOH. Finally, it was found that DCM/MeOH was the bestcombination for extraction, because the DCM can best swell the PS resinswhile MeOH still readily dissolves the metal salts. Metal salts of Cu²⁺,Mn²⁺, and Ni²⁺ were used in extraction studies. Solutions containingthese metal cations were prepared using copper acetate, manganeseacetate, and nickel nitrate salts in a 50:50 solution of DCM/MeOH. Todetermine extraction capability, 3 ml of a prepared solution of 2×10⁻⁴mol/L Cu²⁺ was mixed with 5 mg, 10 mg, 15 mg, 20 mg prepared PLG1(2)(The molar ratio of Cu²⁺ to PLG1(2) was 1:3, 1:6, 1:9, 1:12.)respectively at room temperature with stirring for 40 min. Theextraction results for Cu²⁺ metal are shown in FIG. 3. It was found that20 mg PLG1 and PLG2 resins may completely extract 3 ml Cu²⁺2×10⁻⁴ mol/Lsolution at 40 min. Further optimization of extracting time using 20 mgPLG1 and PLG2 resins with 3 ml 2×10⁻⁴ mol/L concentration copper cationssolution at room temperature (FIG. 4) showed that the shortest time for100% extraction was 30 min. Complexed resin can be directly filtered offto separate from the organic solvent.

For nickel, 20 mg of prepared PLG1 or PLG2 was mixed with 3 ml of thenickel (2×10⁻⁴ mol/L) salt solution at room temperature. After 24 hours,only 30% of nickel was extracted, and after 72 hours, only 45.7% of thenickel was extracted. (The final metal ion concentrations weredetermined using atomic absorption.) For Mn, the Mn salt solution mustbe prepared as a 1×10⁻⁴ mol/L solution, because the detection limit forMn by atomic absorption using a hollow cathode lamp is limited. A 3ml1×10⁻⁴ mol/L manganese salt solution was extracted at room temperatureby 10 mg PLG1 and PLG2 resins for 24 hours. It was found that 63.0% ofthe manganese was removed by the resin, This lead to a surprisingconclusion. The PLG1 and PLG2 resins might selectively extract Cu²⁺within a short time (30 min). To confirm this, 3 ml 2×10⁻⁴ mol/L Cu²⁺and 3 ml 2×10⁻⁴ mol/L Ni²⁺ solution were combined to prepare a 6 ml1×10⁻⁴ mol/L Cu²⁺ and Ni²⁺ mixed solution; 3 ml 2×10⁻⁴ mol/L Cu²⁺solution and 3 ml 1×10⁻⁴ mol/L Mn²⁺ solution were combined to obtain a 6ml 1×10⁻⁴ mol/L Cu²⁺ and 5×10⁻⁵ mol/L Mn²⁺ solution. To these mixedsolutions, 20 mg of the prepared PLG1 and PLG2 resin was added at roomtemperature and allowed to extract for 45 min. After filtering off thePLG1 and PLG2 resins, the extraction solution were analyzed by atomicabsorption. It was found that 80.0% of the Cu²⁺ was removed, but only7.8% Ni²⁺ in the Cu²⁺/Ni²⁺ solution, and only 22.0% Mn²⁺ was extractedin the Cu²⁺/Mn²⁺ mixed solutions.

For the recovery of copper from the PLG1Cu and PLG2Cu resins, severaldifferent conditions were tried (Scheme 8). Routine cleavage or recoveryconditions, DCM with different organic acids including trifluoroaceticacid were not found to release copper ions, nor were strong bases.

Because sodium triacetoxyborohydride can efficiently reduce the iminegroup (C═N) to amino group (C—N) which coordinates only weakly with themetal, the 20 mg PLGICu and PLG2Cu resins were mixed with 3 mlDCM/CH₃COOH (2:1). To this, 10 mg sodium triacetoxyborohydride wasadded, and the reaction progress was measured over time (FIG. 5). Theresults show that after 4 hours the maximum amount of Cu²⁺ can berecovered (70.0%). Extending the reaction time or increasing the amountof sodium triacetoxyborohydride does not increase this recovery rate.

To conclude, an optimized synthetic route for resins PLG1 and PLG2 wasobtained. This kind of resin can selectively extract copper (II) cationwithin short time. The copper can then be recovered using reducingconditions from the resin. This has the potential to enable theselective extraction of copper even from a mixture containing othermetals. PLG1 and PLG2 resins could also be applied in environmental ormaterials chemistry to remove copper or in combinatorial chemistry as ametal scavenging agent to remove excess copper. In the future, designnew solid reagents to selectively extract other metals or improve on theselectivity or application of this system.

Experimental

All organic solvents were from Sigma-Aldrich Co. and were used directlyfor synthesis. Metal salts and other reagent for synthesis were fromAcros Organics Co. Polystyrene (PS) aminomethyl resin (1% DVB, 0.59mol/g loading and 100-200 mesh.) was from ChemPep Inc. IR, Prestige-21Fourier transform infrared spectrophotometer and KBr solid samples.Atomic absorption spectrum (VarianAA240), its software (AA240FS) andhollow cathode lamp (HLC; Ni 232.0 nm, optimum working range: 0.1-20mg/L; Mn 279.5 nm, optimum working range: 0.02-5 mg/L; Cu 324.8 nm,optimum working range: 0.03-10 mg/L) from Varian, Inc.

Example 5 References

-   1. Zhao, J.; Han, B.; Zhang, Y.; Wang, D. Anal. Chim. Acta 2007,    603, 87.-   2. Jeanneau, L.; Faure, P.; Jarde, E. J. Chromatography A. 2007,    1173, 1.-   3. Tokuyama, H.; Iwama, T.; Langmuir, ASAP.-   4. Vanloot, P.; Branger, C.; Margaillan, A.; Brach-Papa, C.;    Boudenne, J. L.; Coulomb, B. Anal. Bioanal. Chem. 2007, 389, 1595.-   5. Divrikli, U.; Akdogan, A.; Soylak, M.; Elci, L. J. Haz. Materials    2007, 149, 331.-   6. Cui, Y.; Chang, X.; Zhu, X.; Luo, H.; Hu, Z.; Zou, X.; He, Q.    Microchemical Journal 2007, 87, 20.-   7. Duran, C.; Gundogdu, A.; Bujut, V. N.; Soylak, M.; Elci, L.;    Senturk, H. B.; Tufekci, M. J. Haz. Mat. 2007, 146, 347.-   8. Musteata, M. L.; Musteata, F. M.; Pawliszyn, J. Anal. Chem. 2007,    79, 6903.-   9. Grigoriadou, D.; Androulaki, A.; Psomiadou, E.; Tsimidou, M. Z.    Food Chem. 2007, 105, 675.-   10. Rodrigues, C. I.; Marta, L.; Maia, R.; Miranda, M.; Ribeirinho,    M.; Maguas, C. J. Food Comp. Anal. 2007, 20, 440.-   11. Pohl, P.; Prusisz, B. Food Chem. 2007, 102, 1415.-   12. Sanvicens, N.; Moore, E. J.; Guilbault, G. G.; Marco, M. P.; J.    Agric. Food Chem. 2006, 54, 9176.-   13. Basheer, C.; Chong, H. G.; Hii, T. M.; Lee, H. K. Anal. Chem.    2007, 79, 6845.-   14. I. Wilson, D. Anal. Chem. 1987, 59, 2830.-   15. Zhang, W.; Lu, Y.; J. Comb. Chem. 2007, 9, 836.-   16. Curran, D. P.; Luo, Z.; J. Am. Chem. Soc. 1999, 121, 9069.-   17. Matsugi, M.; Curran, D. P. Org. Lett. 2004, 6, 2717.-   18. Yang, P.; Cao, Y.; Hu, J. C.; Dai, W. L.; Fan, K. N. Applied    Catalysis A: General 2003, 241, 363-   19. Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9, 3595.-   20. Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 14988.-   21. Lee, D.; Yun, J. Tetrahedron Lett. 2005, 46, 2037-2039.-   22. Biffis, A.; Filippi, F.; Palma, G.; Lora, S.; Macca, C.;    Corain. B. J. Mol. Cat. A: Chemical 2003, 203, 213-220.-   24. Wu, X. H.; Gorden, A. E. V. J. Comb. Chem. 2007, 9, 601.-   25. Wu, X. H.; Gorden, A. E. V.; Tonks, S. A.; Vilseck, J. Z. J.    Org. Chem. 2007, 72, 8691.-   26. Holbach, M.; Weck, M. J. Org. Chem. 2006, 71, 1825.-   27. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.    A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.

Example 6

Wu et al., “2-Quinoxalinol Salen Copper Complexes for Oxidation of ArylMethylenes,” Eur. J. Org. Chem., Volume 2009 Issue 4, Pages 451-454, 13Jan. 2009, the content of which is incorporated herein by reference inits entirety.

Abstract

A copper (II) complex of the 2-quinoxalinol salen ligand (salqucu) 1 hasbeen tested for use in catalysis. Here, an optimized method foroxidation of aryl methylenes and its potential applications aredescribed. In organic solvents, the yields obtained are higher thanother commonly used catalytic methods. Because this methods does notrequire high heat or increased pressure, this presents an opportunityfor more environmentally friendly or “green” chemistry in a single phasesystem. Using this method, a key fragment of natural products Vitamin K₁and K₂, 1,4-naphthoquinone, can be synthesized from 1,2,3,4-tetra-hydronaphthalene in increased yield (65%) as compared toestablished methods (30-40% yield) that require higher temperatures andincreased pressure.

Introduction

The development of new metal catalysts has been of wide interest insynthetic methodology; however, the application of these in thepharmaceutical industry has been limited for many reasons. Developingless-expensive, easier to use, or more environmentally friendly metalcatalysts is a promising trend for new synthetic methods. The oxidationof C—H bonds offers benefits in commercial organic synthesis in the formof “greener” chemistry by energy efficiency, and operational simplicity,while at the same time reducing wastes. Salen metal (Mn, Ru, Co, Cu,etc.) complexes have been used in the development of catalysts fornumerous reactions, among these the oxidation of activated C—H bonds;however, this reaction is limited by low solubility of salen ligands inorganic solvents resulting in low yields. For these reasons, a modifiedsalen system that can be used for oxidation of activated C—H bonds isuseful.

Previously, several methods of oxidation of aryl methylenes to form arylcarbonyls or aryl α-hydroxyl groups have been described. The utility ofthese systems has often been limited by the need for selectivity. In the1970's, researchers used Se₂O as the oxidant for reactions like this;however, the mechanism was determined to proceed with the formation ofβ-ketoseleninic acids leading to numerous byproducts. Oxidations withmanganese salts or nitropyridinium salts were found to have a hydrogentransfer and radical mechanism, but these resulted in low yields (lessthan 60%). Singlet oxygen has also been investigated for use as anoxidant, but because this reaction also involves radical mechanism, theproducts are a mixture of the α-keto and α-hydroxyl group products. Morerecently, methods of oxidation using hypervalent iodine,tert-butylhydroperoxide, Jones reagent, DDQ, or peroxyacid have beenreported. Yields of these methods are still less than 80%, and thesemethods require rigorous controlled conditions.

For this kind of oxidation, catalysts are required for acceleration ofthe reaction and improvement of yields. Metal catalysts used in this wayhave included copper, cobalt or ruthenium salts. For this purpose, salenligands have been used as manganese or copper catalyst supports. Onepromising method developed recently is the Gif system, in which an ironcatalyst is combined with a suitable carboxylic acid, pyridine, zincdust (as a reductant) with oxygen as the oxidant, to acylate methylene;however, less than 40% yields were obtained. Many articles have reportedhigh conversion rates of this oxidation as determined by GC or HPLC;however, this is not a good reflection of isolable yields, due to thedifferent absorptions between starting materials and products. This isespecially true in the oxidation of an aryl methylene group into an arylcarbonyl group which should exhibit a stronger UV absorption. For thisparticular oxidation, it is difficult to identify a metal catalystpossessing both good solubility in organic polar aprotic solvents (forexample, CH₃CN) and non polar solvents (for example, hexane), abottleneck to the oxidation of non polar compounds like steroids.

Based on the 2-quinoxalinol salen ligands (salqu), a new coppercatalyst, salquCu 1 (FIG. 6) was developed. This metal complex can beused as a catalyst in the conversion of aryl methylene groups into arylcarbonyl groups. Described here is a method of using this catalyst, andits selectivity is characterized. Potential applications of the salquCucatalyst 1 are proposed

Results and Discussion

The conversion of diphenylmethane into benzophenone was selected to testthe activity of catalyst salqucu 1 and to develop optimized conditions.Based on previous reports with salphCu, three equivalents of H₂O₂ inCH₃CN as solvent with 1% by molar of the catalyst salquCu 1 was heatedto reflux temperature for 18 hours. Under these conditions, the isolatedyield of benzophenone was only 27%. Six experimental factors wereconsidered to optimizing this reaction:oxidant (FIG. 7), catalyst ratio(FIG. 8), reaction time (FIG. 9), oxidant ratio (FIG. 10), solvent, andtypes of catalyst (FIG. 11 and Table 10).

First, four oxidants were tested using CH₃CN as solvent in each case,with 1% of catalyst 1 at reflux temperature for 18 hours. (FIG. 7) Itwas found that tert-butylhydroperoxide in decane was the best oxidant,quantitatively converting diphenylmethane into benzophenone. Whentert-butylhydroperoxide in water was used as the oxidant, the yield ofproduct, benzophenone, was around 80%. (FIG. 7) The use oftert-butylhydroperoxide in decane allows for a uniform or monophasicorganic soluble catalyst system, and thus further improves the optimalyield.

With tert-butylhydroperoxide in decane as oxidant, the catalyst ratiowas increased from 0.1% to 3% (Their turnover numbers are 736, 176, 99and 32 respectively.) It was found that 1% of catalyst 1 was best forthis oxidation. (FIG. 8) Although 0.1% catalyst 1 leads to the highestturnover number, using 1% catalyst 1 results in the optimal yieldswithin 18 hours. Increasing the amount of catalyst beyond this point didnot decrease the reaction time required to achieve the optimal yield ofbenzophenone. Using less than 1% catalyst resulted in reduced yields.(FIG. 8) Decreasing the reaction time or oxidant ratio also results inlower yields. (FIGS. 9 and 10) The addition of more of thetert-butylhydroperoxide oxidant also does not serve to decrease thereaction time. (FIG. 10)

Finally, several polar and non polar solvents were tested. Withacetonitrile, chloroform, toluene and hexane as solvents, the yields ofthe desired product, benzophenone, were very high (over 95%), but usingTHF as solvent, the yields were very low, because of the degradation ofTHF under oxidative conditions. When toluene was used as solvent, therewere not any byproducts generated by reaction of the toluene obtained.Therefore, the optimal reaction conditions require acetonitrile(toluene, hexane or chloroform) as solvent, the addition of 3equivalents of tert-butylhydroperoxide in decane as oxidant, with 1% ofthe catalyst salquCu 1. The reaction mixture heated to refluxtemperature and found to be complete after 18 hours.

Previously, a library of salqu ligands has been prepared usingcombinatorial methods. These have been used to prepare stable metalcomplexes of broad solubility with Ni²⁺, Co²⁺, Cu²⁺, Mn or UO₂ ²⁺.Different metal complexes were tested as catalysts. (FIG. 6)

Without the addition of catalyst, oxidation using 3 equivalents oftert-butylhydroperoxide in decane as oxidant in acetonitrile heated toreflux temperature for 18 hours, resulted in a very modest yield. Onlyabout 5-10% of the desired product, benzophenone, was obtained. With theaddition of copper salts to the reaction mixture, 50-60% benzophenonecan be obtained. The addition of the salph Cu complex 6 increased theyield of benzophenone obtained to 74%. Using the salen Mn complex 7,produced a similar result, 75%.

Why using the catalysts 6 and 7 results in lower yields than catalystsalquCu 1 remains unclear, but two possibilities come to mind. Judgingfrom the uranyl (UO₂ ²⁺) crystal structure, the salqu metal complexes(1-5) have a slightly different metal coordination geometry than thesalph (6) and salen complexes (7). The salqu ligand in the uranyl (UO₂²⁺) metal complex is puckered and has the metal lifted above the planeof the ligand while the salen and salph (6) and salen complexes (7) areplanar. The salqu complexes also have improved solubility in numerousorganic solvents. Either characteristic of these complexes could affectthe catalytic reaction mechanism and lead to the observed improvedyields. The improved solubility of catalyst salquCu 1 also eliminatesthe need for a biphasic system, which would be useful in applying thissystem to larger scale applications.

As a demonstration of the importance of solubility toward the efficacyof this reaction, different salqu copper complexes were examined incatalytic studies. The results of these experiments are depicted inTable 10.

TABLE 10 Optimized conditions with different salquCu catalysts (1x).

No. R¹ R² Yield (%)^([a]) 1 CH₂Ph 3,5-ditertbutyl 99 1a CH₂Ph3-tert-butyl 92 1b CH₂CH(CH₃)₂ 3,5-ditertbutyl 99 1c CH₂CH(CH₃)₂ H 90 1dCH₂CH(CH₃)₂ 5-OH 80 1e CH(CH₃)₂ H 90 1f CH(CH₃)₂ 5-OH 65 1g CH₂CH₂SCH₃3-OH 77 ^([a])Yields are based on separation by flash columnchromatography and mass calculation.

Besides catalyst 1, tert-butyl functionalized copper complexes 1a and 1bshow good catalytic effect, whereas hydroxyl functionalized complexes ifand 1g lead to yields comparable with regular the manganese salen andcopper salph complexes 6 and 7. It is also possible that the hydroxylgroup impairs the catalytic function of Cu or Mn, leading to the loweryields. Complexes 1c and 1e gave a lower yield than catalysts 1, 1a and1b, probably because of reduced solubility.

Catalyst (1) is stable to air and moisture and can be reused at leasttwice. Catalysts that are found to be stable both to air and moistureare much more convenient for their application. Stable capability wastested using the reaction conditions to oxidize diphenylmethane.

Diphenylmethane was reacted with 1% catalyst 1 and 3 equivalentstert-butylhydroperoxide in refluxing acetonitrile for 18 hours. After 18hours, an additional equivalent of diphenylmethane, and 3 equivalentsoxidant were added into reaction system. The reaction mixture wasallowed to continue refluxing for another 18 hours. After this period oftime, the addition was repeated. Finally, the pure benzophenone productwas obtained by flash column chromatography. The total yield was over95% of the combined amounts of starting material. While the addition ofadditional material in the initial reaction (lowering the % catalystpresent) reduces the yield produced in 18 hours, the addition ofadditional materials in increments indicates that the catalytic speciesis regenerated during the course of the reaction and that the catalyst 1was reused at least twice. This increases the overall lifetime of theusable catalyst and could be of benefit to reduce volumes of solventsrequired in larger scale reactions.

Once the optimal conditions were determined, these were used inreactions with several compounds containing aryl methylene group to beoxidized (Table 11).

TABLE 11 Tested Aryl methylene compound using catalyst 1. Entry^([a])Starting material Final product Yield (%))^([f]) 1

99^([c]) 2

88^([c]; [e]) 3

93^([c]) 4

50^([c]); 90^([d]) 5

14^([c]); 82^([d]) 6

80^([c]) 7

81^([c]) 8

80^([c]) 9

47^([c]) 10

26^([d] 66[d])

11

60^([c]); 91^([d]) 12

—^([b]) 13

—^([b]) 14

—^([b]) 15

—^([b]) 16

—^([b]) 17

56^([c]) 18

66^([c]) ^([a])All of products were characterized by ¹H and ¹³C NMR andfound to be in agreement with their standard NMR spectrum. ^([b])None ofthe expected final product was obtained. ^([c])Method 1: 1% catalyst 1,CH₃CN, 3 equivalents t-BuOOH (in decane), reflux for 18 hours.^([d])Method 2: (1) 1% catalyst 1, CH₃CN, 3 equivalents t-BuOOH (indecane), reflux for 18 hours. (2) 3 equivalents t-BuOOH (in decane),CH₃CN, reflux for 18 hours. ^([e])After 40 minutes the Schiff baseproduct, N-benzylidenebenzylamine was formed. 89% of benzaldehyde wasdetermined by adding the reacted benzaldehyde with pure isolatedbenzaldehyde. ^([f])Yields are based on separation by flash columnchromatography and mass calculation.

It was found that if there is an electron donor group neighbouring tothe methylene group to be oxidized, the yield is increased (Entry 1, 2and 3), whereas if there is a neighbouring electron withdrawing groupthe yield will decrease (Entry 4, 5). Aryl methylene compounds withneighbouring electron withdrawing groups can be oxidized again toenhance the final yields (Table 11, Method 2). Aryl methylene groups canbe selectively oxidized, while other methylene groups were not affected(Entry 6). If an amino or hydroxyl group is present neighbouring to themethylene group, the final product produced is an aldehyde (Entry 2 andEntry 9). By this method, not only may the aryl methylenes be oxidizedto the corresponding carbonyl groups, but an ether group can beconverted to an ester in good yields (Entry 3).

If there is no aryl group neighbouring the methylene group, the expectedproduct is not obtained (Entry 16). This could also be due to stericlimitations on the configurational geometry of the metal complex to thecatalytic mechanism. For example, when there is a bulky tert-butyl groupon the methylene, none of the expected product found (Entry 13, 14).Compounds containing a hydroxyl group were found to have no reaction(Entry 15) or lower yields (Entry 9), presumably because the oxygen atomcould coordinate with the catalyst metal centre, (in this case copper),and this may block the catalyst mechanism. Remarkably,tetra-hydroisoquinoline and tetra-hydroquinoline were special cases.Oxidation of tetra-hydroisoquinoline and tetra-hydroquinoline using thismethod leads to isoquinoline and quinoline (Entry 17 and 18respectively), but not α-ketoisoquinoline or α-ketoquinoline analogs.For some of the oxidation reactions found to have poor yields, the yieldcan be improved using a modified reaction scheme, method 2. (Entry 4, 5,10 and 11).

The oxidation of benzylamine directly into benzaldehyde by the catalyst1 mimics the important biological process of oxidation of aminesubstrates to aldehydes as catalyzed by the naturally occurringmetalloenzymes that contain copper, namely amine and lysyl oxidases(Entry 2). Once the benzaldehyde is generated, this can react directlywith any remaining unreacted benzylamine to formN-benzylidenebenzylamine. N-benzylidenebenzylamine is a useful, costlybut commercially available, indicator reagent used for organolithiumassays and as an intermediate of amino acid syntheses, and this is apotentially useful as an inexpensive method to prepareN-benzylidenebenzylamine directly from benzylamine.

In another example of the potential utility of this catalyst,1,4-naphthoquinone is typically prepared on an industrial scale fromnaphthalene using oxygen gas with a vanadium catalyst at hightemperature while under pressure. This reaction typically yields no morethan 40%. This is an important compound as it is a key intermediate ofseveral natural products including phylloquinone and menaquinone(vitamin K₁ and K₂), the derivatives of which have been found to havebroad bioactivity ranging from anticancer to antifungal. Several newmethods for preparing 1,4-naphthoquinone derivatives have beendeveloped, but all of them involve more expensive metal catalysts.Disclosed here is a new method for preparing 1,4-naphthoquinone by usinginexpensive commercial available starting material1,2,3,4-tetrahydronaphthalene and salquCu catalysts 1 with 63% yield.(Entry 10) This conversion also mimics another crucial biologicaloxidization process catalyzed by galactose oxidase.

This is a promising new result, but it remains to determine the specificoxidation mechanism, although the mechanism of oxidation by copper saltand THBP has been investigated. This can be difficult, because if themechanism involves a carbon cation intermediate, the methoxyl groupshould be better leaving group than hydrogen (Entry 3) in conversion ofphenyl methyl ether to methyl benzoate. In contrast, in the reactionscharacterized here the hydrogen acts as the leaving group. Secondly, ifthe mechanism involves a radical intermediate, the conversion of1,1-diphenylproane to benzophenone can not be explained and the expectedproducts 1,1-diphenylproanol should be obtained as a final reasonableproduct. (Entry 7) In addition, conversion of tetra-hydroquinoline toquinoline, expected α-ketoquinolines have not been obtained, indicatingan unexpected mechanism occurs. (Entry 17 and 18) Another question thatarises is in the case of benzylamine. (Entry 2) The expected productwould be benzoic amide; however, the major product found is benzaldehydein very good yield (>88%).

Conclusions

The unusual salqucu metal complex 1 was developed for use in oxidationof aryl methylenes with good yields. Results of the optimization processindicate that the configuration and solubility of salqu copper complexcatalyst (e.g., 1) are key factors during the oxidation. Besides thesalqu copper complex 1, the salqu manganese complex was also found todemonstrate catalytic ability.

Using the copper catalyst 1, an important fragment of natural compound,1,4-naphthoquinone, can be obtained in high yields, and the oxidationsof the metalloenzymes amine oxidase and galactose oxidase, can bemimicked. These types of catalysts present a new option for use inindustry or organic syntheses because of their relative ease ofpreparation, low sensitivity to moisture and air, and the use of moreenvironmentally friendly and less costly metals. They are also solublein many common organic solvents. They possess high catalytic efficiencyand can be reused at least twice. The salqu metal complexes disclosedhere (e.g., 1) may be particularly useful after incorporation intopolymers for use in solid phase catalysts based on the developed solidphase extraction (SPE) technology.

Experimental Section

All of starting materials were purchased from Acros Organics Co., TCI orAlfa Aesar Inc and were used as received. The tert-butylhydroperoxide indecane (6M) and salen Mn complex 7 used were purchased fromSigma-Aldrich Co. Salqu ligands were synthesized by previous procedurepublished. Solvents were purchased from Thermo Fisher Scientific Co. andwere used directly. ¹H and ¹³C NMR spectra were recorded on Bruker AC250 spectrometer (operated at 250 and 62.5 MHz, respectively) or BrukerAV 400 spectrometer (operated at 400 and 100 MHz, respectively). Thefinal synthesized products (Entry 1 to 19) were identified by TLC, 1Hand ¹³CNMR and compared with TLC, ¹H and ¹³CNMR of commerciallyavailable compounds. The known ¹H and ¹³C-NMR of commercial availablecompounds are available from spectral database for organic compounds(SDBS), National Institute of Advanced Industrial Science and Technology(AIST), Japan. Chemical shifts are reported as δ values (ppm). NMR datawere collected by using CDCl₃ or DMSO-d⁶. The solvents used are indictedin the experimental details. Reaction progress was monitored bythin-layer chromatography (TLC) using 0.25 mm Whatman Aluminum silicagel 60-F254 precoated plates with visualization by irradiation with aMineralight UVGL-25 lamp. The products yields are based on separation byflash column chromatography.

Method 1

The synthesis of the products depicted in Table 11 began with thecombination of catalyst 1 (0.02 mmol, 15.2 mg) and 2.0 mmol of startingmaterial (aryl methylene compound) dissolved in 2.0 mL acetonitrile with11.0 mL tert-butylhydroperoxide decane solution (6.0 mmol). The reactionmixture was allowed to stir for 18 hours at 70° C. and monitored by TLC.Once the starting material can no longer be seen by TLC, the reactionwas considered complete. Pure products were obtained using flash columnchromatography with a solution of hexane:ethyl acetate, 10-20:1 as theeluent. The yields of final pure products were from 45-99%. (Seenotation in Table 11.)

Method 2

For reactions found to result in low yields (see Table 11), a modifiedprocedure was employed. The procedure began with of the addition ofcatalyst 1 (0.02 mmol, 15.2 mg) and 2.0 mmol of starting materials (arylmethylene compounds) dissolved in 2.0 mL acetonitrile and 11.0 mLtert-butylhydroperoxide decane solution (6.0 mmol). The reaction mixturewas allowed to stir for 18 hours at 70° C. After 18 hours, an additional1.0 mL tert-butylhydroperoxide decane solution (6.0 mmol) was added andthe solution was heated at reflux temperature for an additional 18hours. The reaction was monitored by TLC. Once the starting material canno longer be seen by TLC, the reaction was considered complete. Pureproducts were obtained by purification using flash column chromatographywith a solution of hexane:ethyl acetate, 10-20:1 as eluent. The yieldsof final pure products were from 65-92%. (See notation in Table 11.)

Data Section

Entry 1—¹H-NMR (400 MHz, CDCl₃): δ 7.49 (t, 4H), 7.62 (t, 2H), 7.84 (d,4H). ¹³C-NMR (100 MHz, CDCl₃): δ 196.8, 137.6, 132.5, 130.1, 128.3.

Entry 2—N-benzylidenebenzylamine: ¹H-NMR (400 MHz, CDCl₃): δ 4.87 (s,2H), 7.28-7.93 (m, 10H), 8.43 (s, 1H). ¹³C-NMR (100 MHz, CDCl₃): δ162.5, 139.0, 136.4, 134.5, 130.9, 130.6, 64.9. Benzaldehyde: ¹H-NMR(400 MHz, CDCl₃): δ 7.50 (t, 2H), 7.60 (t, 1H), 7.86 (d, 2H), 10.01 (s,1H). ¹³C-NMR (100 MHz, CDCl₃): δ 191.9, 136.0, 134.0, 129.3, 128.6.

Entry 3—¹H-NMR (400 MHz, CDCl₃): δ 3.91 (s, 3H), 7.43 (t, 2H), 7.53 (t,1H), 8.05 (d, 2H). ¹³C-NMR (100 MHz, CDCl₃): δ 167.1, 132.9, 130.2,129.6, 128.4, 128.2, 126.9, 52.0.

Entry 4—¹H-NMR (250 MHz, CDCl₃): δ 2.71 (s, 3H), 8.15 (d, 2H), 8.35 (d,2H). ¹³C-NMR (62.5 MHz, CDCl₃): δ 196.3, 141.4, 129.3, 123.9, 27.0.

Entry 5—¹H-NMR (400 MHz, CDCl₃): δ 1.43 (t, 3H), 4.60 (q, 2H), 7.53 (t,2H), 7.67 (t, 1H), 8.01 (d, 2H). ¹³C-NMR (100 MHz, CDCl₃): δ 186.5,163.9, 134.9, 132.4, 130.0, 128.9, 62.4, 14.1.

Entry 6—¹H-NMR (400 MHz, CDCl₃): δ 1.02 (t, 3H), 1.97 (m, 2H), 2.96 (t,2H), 7.46 (t, 2H), 7.53 (t, 1H), 7.96 (d, 2H). ¹³C-NMR (100 MHz, CDCl₃):δ 200.4, 137.1, 132.9, 128.4, 128.2, 128.0, 40.5, 27.2, 13.9.

Entry 7—¹H-NMR (400 MHz, CDCl₃): δ 7.50 (t, 4H), 7.62 (t, 2H), 7.85 (d,4H). ¹³C-NMR (100 MHz, CDCl₃): δ 196.8, 137.6, 132.4, 130.1, 128.3.

Entry 8—¹H-NMR (400 MHz, CDCl₃): δ 2.57 (s, 3H), 7.49 (t, 2H), 7.60 (t,1H), 7.94 (d, 2H). ¹³C-NMR (100 MHz, CDCl₃): δ 198.4, 137.3, 133.6,129.1, 128.6, 27.2.

Entry 9—¹H-NMR (400 MHz CDCl₃): δ 7.50 (t, 2H), 7.60 (t, 1H), 7.86 (d,2H), 10.01 (s, 1H). ¹³C-NMR (100 MHz, CDCl₃): δ 191.9, 136.0, 134.0,129.3, 128.6.

Entry 10—¹H-NMR (400 MHz, DMSO-d⁶): δ 7.02 (s, 2H), 7.80 (dd, 2H), 8.13(dd, 2H). ¹³C-NMR (100 MHz, DMSO-d⁶): δ 185.1, 138.7, 134.0, 131.9,126.5.

Entry 11—¹H-NMR (250 MHz, CDCl₃): δ 2.71 (s, 3H), 7.56 (m, 2H), 7.62 (m,4H), 8.05 (s, 1H). ¹³C-NMR (62.5 MHz, CDCl₃): δ 198.1, 135.6, 134.4,132.5, 130.2, 129.6, 128.5, 128.4, 127.8, 126.8, 123.9.

Entry 17—¹H-NMR (400 MHz, CDCl₃): δ 7.57-7.96 (m, 5H), 8.54 (d, 1H),9.27 (s, 2H). ¹³C-NMR (100 MHz, CDCl₃): δ 152.5, 142.9, 135.8, 130.4,127.6, 127.3, 126.5, 120.5.

Entry 18—¹H-NMR (400 MHz, CDCl₃): δ 7.29 (m, 1H), 7.47 (t, 1H), 7.63 (t,1H), 7.73 (d, 1H), 8.06 (m, 2H), 8.60 (m, 1H). ¹³C-NMR (100 MHz, CDCl₃):δ 150.3, 148.2, 136.0, 129.4, 128.2, 127.8, 126.5, 121.0.

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It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the scope and spirit of the invention. Theinvention illustratively described herein suitably may be practiced inthe absence of any element or elements, limitation or limitations whichis not specifically disclosed herein. The terms and expressions whichhave been employed are used as terms of description and not oflimitation, and there is no intention that in the use of such terms andexpressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the invention. Thus, itshould be understood that although the present invention has beenillustrated by specific embodiments and optional features, modificationand/or variation of the concepts herein disclosed may be resorted to bythose skilled in the art, and that such modifications and variations areconsidered to be within the scope of this invention.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member, any subgroup of members of theMarkush group or other group, or the totality of members of the Markushgroup or other group.

Citations to a number of patent and non-patent references are madeherein. The cited references are incorporated by reference herein intheir entireties. In the event that there is an inconsistency between adefinition of a term in the specification as compared to a definition ofthe term in a cited reference, the term should be interpreted based onthe definition in the specification.

1. A compound having a formula:

wherein: R₁ is an amino acid side chain moiety; and R₂ and R₃ arehydrogen, hydroxyl, C₁₋₆ alkyl which may be straight chain or branched,C₁₋₆ alkoxy which may be straight chain or branched, ether, or amine;and R₂ and R₃ are the same or different.
 2. The compound of claim 1,wherein R₁ is selected from:


3. The compound of claim 1, wherein R₁ is selected from:


4. The compound of claim 1, wherein R₁ is an aromatic amino acid sidechain moiety.
 5. The compound of claim 1, wherein R₂ and R₃ are thesame.
 6. The compound of claim 1, wherein R₂ and R₃ are different. 7.The compound of claim 1, wherein at least one of R₂ and R₃ are hydrogen.8. The compound of claim 1, wherein both of R₂ and R₃ are hydrogen. 9.The compound of claim 1, wherein at least one of R₂ and R₃ are hydroxyl.10. The compound of claim 1, wherein both of R₂ and R₃ are hydroxyl. 11.The compound of claim 1, wherein at least one of R₂ and R₃ is 3-OH. 12.The compound of claim 1, wherein at least one of R₂ and R₃ is 5-OH. 13.The compound of claim 1, wherein at least one of R₂ and R₃ is 3-C₁₋₆straight chain or branched alkyl.
 14. The compound of claim 1, whereinboth of R₂ and R₃ are 3-C₁₋₆ straight chain or branched alkyl.
 15. Thecompound of claim 1, wherein at least one of R₂ and R₃ is 3-tert-butyl16. The compound of claim 1, wherein at least one of R₂ and R₃ is3,5-Di-tert butyl.
 17. The compound of claim 1 complexed to a divalentcation.
 18. The compound of claim 1, wherein the divalent cation isselected from a group consisting of Cu²⁺, Mn²⁺, Co²⁺, Ni²⁺, and UO₂ ²⁺.19. The compound of claim 1, conjugated to a solid support.
 20. Thecompound of claim 19, wherein the solid support is a functionalizedpolystyrene resin selected from a group consisting of aminomethylpolystyrene resin, 2-chrlotrityl chloride resin, DHP HM resin, HMPA-AMresin, Knorr resin, Knorr-2-chlorotrityl resin, MBHA resin, Merrifieldresin, oxime resin, PAM resin, Rink amide-AM resin, Rink amide-MBHAresin, Sieber resin, Wang resin, Weinreb AM resin, Boc-Ser-Merrifieldresin, and Boc-Gly-Merrifield resin.
 21. The compound of claim 1,wherein the compound is conjugated via an acylating linker compound. 22.The compound of claim 21, wherein the acylating linker compound is ananhydride compound.
 23. The compound of claim 22, wherein the anhydridecompound is an acid anhydride.
 24. The compound of claim 1, conjugatedto a fluorophore.
 25. A method of making the compound of claim 1,comprising reacting a mixture comprising a 2-quinoxalinol compoundhaving a formula:

wherein R₁ is an amino acid side chain moiety; and a salicylic aldehydecompound having a formula:

wherein R₂ is hydrogen, hydroxyl, C₁₋₆ alkyl which may be straight chainor branched, C₁₋₆ alkoxy which may be straight chain or branched, ether,or amine.
 26. The method of claim 25, wherein the mixture furthercomprises an alcohol and reacting the mixture comprises heating themixture.
 27. A method of removing a divalent cation from a solution,comprising contacting the solution with the compound of claim
 1. 28. Themethod of claim 27, wherein the divalent cation is selected from a groupconsisting of Cu²⁺, Mn²⁺, Co²⁺, Ni²⁺, and UO₂ ²⁺.
 29. A method ofremoving a divalent compound from a solution, comprising contacting thesolution with the compound of claim
 19. 30. The method of claim 29,wherein the divalent cation is selected from a group consisting of Cu²⁺,Mn²⁺, Co²⁺, Ni²⁺, and UO₂ ²⁺.
 31. A method for detecting a divalentcation in a solution, the method comprising (a) contacting the solutionwith the compound of claim 1, wherein if the solution comprises thedivalent cation, the compound forms a complex with the divalent cation;and (b) detecting the complex in the solution.
 32. The method of claim31, wherein detecting the complex comprises at least one of determiningan absorption maximum for the solution via UV-Vis spectra analysis;detecting a change in fluorescence for the solution; and detecting achange in electrochemical properties of the solution.
 33. A method fordetecting a divalent cation in a solution, the method comprising: (a)contacting the solution with a complex comprising a complexed cation,which complex optionally may be conjugated to a solid support or afluorophore, where if the solution comprises the cation, the solutioncation displaces the complexed cation from the compound and forms a newcomplex with the compound; and (b) detecting the new complex ordetecting the displaced cation.
 34. The method of claim 33, whereindetecting the new complex or displaced cation comprises at least one ofdetermining an absorption maximum for the solution via UV-Vis spectraanalysis; detecting a change in fluorescence for the solution; anddetecting a change in electrochemical properties of the solution.
 35. Amethod of oxidizing a compound comprising reacting the compound with anoxidizing agent and the compound of claim
 17. 36. The method of claim35, wherein the compound is a methylene compound.